Continuing treatment with two common multiple sclerosis (MS) medications during pregnancy is associated with significantly lower relapse rates and few pregnancy-related complications, new research shows. Results of two studies show that preterm birth, spontaneous abortions, and major congenital anomalies were rare with anti-CD20 drugs ocrelizumab or natalizumab, even when continued well into the third trimester. However, hematologic abnormalities were common in newborns who were exposed to MS therapies during pregnancy.

The research comes at a time when the incidence of MS is on the rise worldwide and pregnancy in MS patients is becoming more common (Neurology. 2018 Oct 23;91[17]:e1559-69). “The results of our study should lead to a distinct risk-benefit discussion between neurologists and pregnant natalizumab-treated women to maintain treatment up to the 30th or even the 34th week of gestation, in combination with an early restart during the first 4 weeks after delivery,” Sandra Thiel, PhD, an investigator in one of the studies, told delegates attending the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Dr. Thiel is in the department of neurology at St. Josef Hospital and Ruhr University Bochum (Germany).
 

Rising number of pregnancies

In a second study, researchers from Spain presented results from the largest dataset of pregnancy outcomes for an anti-CD20 therapy in MS. The trial included 2,020 pregnancies, most of which were followed prospectively. The study included data on pregnancies since 2008. The largest single-year increase among participants was in the past year, in which there was a 65% rise in the number of pregnancies.

“The number of women with MS exposed to ocrelizumab before, during, and after the pregnancy is increasing and increasing,” Celia Oreja-Guevara, MD, PhD, vice-chair of neurology and head of the Multiple Sclerosis Center of the University Hospital San Carlos, Madrid, told conference attendees. “We have more evidence, we have more knowledge, patients and physicians trust ocrelizumab more. They know that it’s a safe treatment, and more patients are becoming pregnant.”

Dr. Oreja-Guevara highlighted a decrease in the number of elective abortions, which dropped from 50% in 2021 to 11% in the past year. The number was higher for patients with known exposure to ocrelizumab (11.5% vs. 3.7%).

Among the prospective cases, ectopic pregnancies occurred in 1.8% of those who were not exposed to ocrelizumab versus 1.4% of those exposed to the medication. The overall rate of spontaneous abortion was 11.8%, which, Dr. Oreja-Guevara said, is lower than the rate among the general population in Spain.

In the total cohort, 79.0% of pregnancies resulted in live births. Rates were similar regardless of ocrelizumab exposure. About 57% of births were full term, and 10.0% were preterm. Gestational age was unknown in 32.9% of the cases.

Overall, 0.9% of infants had a major congenital anomaly, which Dr. Oreja-Guevara said is lower than the rate of 2%-3% in all children born in Europe.
 

A look at natalizumab

To examine outcomes following use of natalizumab during pregnancy, researchers examined data from the German Multiple Sclerosis and Pregnancy Registry, which was created in 2006 and follows people during pregnancy and up to 6 years post partum. Of the 350 pregnant people included in the study, 171 continued natalizumab therapy beyond the first trimester. Discontinuation occurred at a median of 30.9 gestational weeks.

Most patients did not experience MS relapse during pregnancy, but the number was higher for patients who continued taking natalizumab later into pregnancy compared with those who stopped taking the drug in the first trimester (94.8% vs. 67.6%).

In the group analysis, women who continued treatment after the first trimester had significantly fewer relapses during pregnancy (5.9% vs. 32.4%; P < .001) and in the postpartum period (22.8% vs. 49.7%, P < .001). Resuming treatment with natalizumab within 4 weeks after birth significantly reduced relapse risk post partum (odds ratio, 0.32; P < .001).

The researchers also examined relapse risk with respect to treatment duration after the first trimester. Significantly more women who discontinued natalizumab before the 30th gestational week experienced postpartum relapses, compared with those whose treatment extended beyond that point (38.5% vs. 16.0%; P = .008), especially during the first postpartum trimester (26.9% vs. 8.00%; P = .009).

There were no significant differences in preterm births or major congenital abnormalities between groups. However, about half of the infants exposed to natalizumab beyond the first trimester were born with anemia or other hematologic abnormalities.

Another unexpected finding was the number of infants who were small for their gestational age (SGA). About 19% of infants born to women who continued treatment later in pregnancy were SGA. Among those in the group that discontinued therapy in the first trimester, the figure was just under 17%.

“Pregnancy outcomes were within the expected range, but a potential increased risk for small for gestational age newborns justified further investigation,” Dr. Thiel said.
 

Reassuring data

Angie Child Jelin, MD, director of the first trimester screening program and associate professor of gynecology and obstetrics at Johns Hopkins University, Baltimore, said that the increase in the number of pregnant patients with MS seen in their clinic could be caused in part by the growing body of work on MS treatment during pregnancy.

“It’s very reassuring that these data have come out and showed how safe they are generally in pregnancy,” Dr. Jalin said.

Although hematologic abnormalities in newborns are thought to be acute, Dr. Jalin said long-term study is needed to better understand any potential lasting effects from those abnormalities, as well as any effects in SGA newborns.

“Long-term outcomes are very hard to acquire, but ideally you’d want long-term outcomes on all of these measures,” Dr. Jalin said.

Funding for the natalizumab study was not disclosed. The ocrelizumab study was funded by F. Hoffmann–La Roche. Dr. Oreja-Guevara received honoraria for consulting and serving on advisory boards from Biogen Idec, F. Hoffmann–La Roche, Genzyme, Merck, Novartis, and Teva. Dr. Thiel has received speaker honoraria from Bayer Healthcare. Dr. Jalin reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Continuing treatment with two common multiple sclerosis (MS) medications during pregnancy is associated with significantly lower relapse rates and few pregnancy-related complications, new research shows. Results of two studies show that preterm birth, spontaneous abortions, and major congenital anomalies were rare with anti-CD20 drugs ocrelizumab or natalizumab, even when continued well into the third trimester. However, hematologic abnormalities were common in newborns who were exposed to MS therapies during pregnancy.

The research comes at a time when the incidence of MS is on the rise worldwide and pregnancy in MS patients is becoming more common (Neurology. 2018 Oct 23;91[17]:e1559-69). “The results of our study should lead to a distinct risk-benefit discussion between neurologists and pregnant natalizumab-treated women to maintain treatment up to the 30th or even the 34th week of gestation, in combination with an early restart during the first 4 weeks after delivery,” Sandra Thiel, PhD, an investigator in one of the studies, told delegates attending the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Dr. Thiel is in the department of neurology at St. Josef Hospital and Ruhr University Bochum (Germany).
 

Rising number of pregnancies

In a second study, researchers from Spain presented results from the largest dataset of pregnancy outcomes for an anti-CD20 therapy in MS. The trial included 2,020 pregnancies, most of which were followed prospectively. The study included data on pregnancies since 2008. The largest single-year increase among participants was in the past year, in which there was a 65% rise in the number of pregnancies.

“The number of women with MS exposed to ocrelizumab before, during, and after the pregnancy is increasing and increasing,” Celia Oreja-Guevara, MD, PhD, vice-chair of neurology and head of the Multiple Sclerosis Center of the University Hospital San Carlos, Madrid, told conference attendees. “We have more evidence, we have more knowledge, patients and physicians trust ocrelizumab more. They know that it’s a safe treatment, and more patients are becoming pregnant.”

Dr. Oreja-Guevara highlighted a decrease in the number of elective abortions, which dropped from 50% in 2021 to 11% in the past year. The number was higher for patients with known exposure to ocrelizumab (11.5% vs. 3.7%).

Among the prospective cases, ectopic pregnancies occurred in 1.8% of those who were not exposed to ocrelizumab versus 1.4% of those exposed to the medication. The overall rate of spontaneous abortion was 11.8%, which, Dr. Oreja-Guevara said, is lower than the rate among the general population in Spain.

In the total cohort, 79.0% of pregnancies resulted in live births. Rates were similar regardless of ocrelizumab exposure. About 57% of births were full term, and 10.0% were preterm. Gestational age was unknown in 32.9% of the cases.

Overall, 0.9% of infants had a major congenital anomaly, which Dr. Oreja-Guevara said is lower than the rate of 2%-3% in all children born in Europe.
 

A look at natalizumab

To examine outcomes following use of natalizumab during pregnancy, researchers examined data from the German Multiple Sclerosis and Pregnancy Registry, which was created in 2006 and follows people during pregnancy and up to 6 years post partum. Of the 350 pregnant people included in the study, 171 continued natalizumab therapy beyond the first trimester. Discontinuation occurred at a median of 30.9 gestational weeks.

Most patients did not experience MS relapse during pregnancy, but the number was higher for patients who continued taking natalizumab later into pregnancy compared with those who stopped taking the drug in the first trimester (94.8% vs. 67.6%).

In the group analysis, women who continued treatment after the first trimester had significantly fewer relapses during pregnancy (5.9% vs. 32.4%; P < .001) and in the postpartum period (22.8% vs. 49.7%, P < .001). Resuming treatment with natalizumab within 4 weeks after birth significantly reduced relapse risk post partum (odds ratio, 0.32; P < .001).

The researchers also examined relapse risk with respect to treatment duration after the first trimester. Significantly more women who discontinued natalizumab before the 30th gestational week experienced postpartum relapses, compared with those whose treatment extended beyond that point (38.5% vs. 16.0%; P = .008), especially during the first postpartum trimester (26.9% vs. 8.00%; P = .009).

There were no significant differences in preterm births or major congenital abnormalities between groups. However, about half of the infants exposed to natalizumab beyond the first trimester were born with anemia or other hematologic abnormalities.

Another unexpected finding was the number of infants who were small for their gestational age (SGA). About 19% of infants born to women who continued treatment later in pregnancy were SGA. Among those in the group that discontinued therapy in the first trimester, the figure was just under 17%.

“Pregnancy outcomes were within the expected range, but a potential increased risk for small for gestational age newborns justified further investigation,” Dr. Thiel said.
 

Reassuring data

Angie Child Jelin, MD, director of the first trimester screening program and associate professor of gynecology and obstetrics at Johns Hopkins University, Baltimore, said that the increase in the number of pregnant patients with MS seen in their clinic could be caused in part by the growing body of work on MS treatment during pregnancy.

“It’s very reassuring that these data have come out and showed how safe they are generally in pregnancy,” Dr. Jalin said.

Although hematologic abnormalities in newborns are thought to be acute, Dr. Jalin said long-term study is needed to better understand any potential lasting effects from those abnormalities, as well as any effects in SGA newborns.

“Long-term outcomes are very hard to acquire, but ideally you’d want long-term outcomes on all of these measures,” Dr. Jalin said.

Funding for the natalizumab study was not disclosed. The ocrelizumab study was funded by F. Hoffmann–La Roche. Dr. Oreja-Guevara received honoraria for consulting and serving on advisory boards from Biogen Idec, F. Hoffmann–La Roche, Genzyme, Merck, Novartis, and Teva. Dr. Thiel has received speaker honoraria from Bayer Healthcare. Dr. Jalin reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Continuing treatment with two common multiple sclerosis (MS) medications during pregnancy is associated with significantly lower relapse rates and few pregnancy-related complications, new research shows. Results of two studies show that preterm birth, spontaneous abortions, and major congenital anomalies were rare with anti-CD20 drugs ocrelizumab or natalizumab, even when continued well into the third trimester. However, hematologic abnormalities were common in newborns who were exposed to MS therapies during pregnancy.

The research comes at a time when the incidence of MS is on the rise worldwide and pregnancy in MS patients is becoming more common (Neurology. 2018 Oct 23;91[17]:e1559-69). “The results of our study should lead to a distinct risk-benefit discussion between neurologists and pregnant natalizumab-treated women to maintain treatment up to the 30th or even the 34th week of gestation, in combination with an early restart during the first 4 weeks after delivery,” Sandra Thiel, PhD, an investigator in one of the studies, told delegates attending the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Dr. Thiel is in the department of neurology at St. Josef Hospital and Ruhr University Bochum (Germany).
 

Rising number of pregnancies

In a second study, researchers from Spain presented results from the largest dataset of pregnancy outcomes for an anti-CD20 therapy in MS. The trial included 2,020 pregnancies, most of which were followed prospectively. The study included data on pregnancies since 2008. The largest single-year increase among participants was in the past year, in which there was a 65% rise in the number of pregnancies.

“The number of women with MS exposed to ocrelizumab before, during, and after the pregnancy is increasing and increasing,” Celia Oreja-Guevara, MD, PhD, vice-chair of neurology and head of the Multiple Sclerosis Center of the University Hospital San Carlos, Madrid, told conference attendees. “We have more evidence, we have more knowledge, patients and physicians trust ocrelizumab more. They know that it’s a safe treatment, and more patients are becoming pregnant.”

Dr. Oreja-Guevara highlighted a decrease in the number of elective abortions, which dropped from 50% in 2021 to 11% in the past year. The number was higher for patients with known exposure to ocrelizumab (11.5% vs. 3.7%).

Among the prospective cases, ectopic pregnancies occurred in 1.8% of those who were not exposed to ocrelizumab versus 1.4% of those exposed to the medication. The overall rate of spontaneous abortion was 11.8%, which, Dr. Oreja-Guevara said, is lower than the rate among the general population in Spain.

In the total cohort, 79.0% of pregnancies resulted in live births. Rates were similar regardless of ocrelizumab exposure. About 57% of births were full term, and 10.0% were preterm. Gestational age was unknown in 32.9% of the cases.

Overall, 0.9% of infants had a major congenital anomaly, which Dr. Oreja-Guevara said is lower than the rate of 2%-3% in all children born in Europe.
 

A look at natalizumab

To examine outcomes following use of natalizumab during pregnancy, researchers examined data from the German Multiple Sclerosis and Pregnancy Registry, which was created in 2006 and follows people during pregnancy and up to 6 years post partum. Of the 350 pregnant people included in the study, 171 continued natalizumab therapy beyond the first trimester. Discontinuation occurred at a median of 30.9 gestational weeks.

Most patients did not experience MS relapse during pregnancy, but the number was higher for patients who continued taking natalizumab later into pregnancy compared with those who stopped taking the drug in the first trimester (94.8% vs. 67.6%).

In the group analysis, women who continued treatment after the first trimester had significantly fewer relapses during pregnancy (5.9% vs. 32.4%; P < .001) and in the postpartum period (22.8% vs. 49.7%, P < .001). Resuming treatment with natalizumab within 4 weeks after birth significantly reduced relapse risk post partum (odds ratio, 0.32; P < .001).

The researchers also examined relapse risk with respect to treatment duration after the first trimester. Significantly more women who discontinued natalizumab before the 30th gestational week experienced postpartum relapses, compared with those whose treatment extended beyond that point (38.5% vs. 16.0%; P = .008), especially during the first postpartum trimester (26.9% vs. 8.00%; P = .009).

There were no significant differences in preterm births or major congenital abnormalities between groups. However, about half of the infants exposed to natalizumab beyond the first trimester were born with anemia or other hematologic abnormalities.

Another unexpected finding was the number of infants who were small for their gestational age (SGA). About 19% of infants born to women who continued treatment later in pregnancy were SGA. Among those in the group that discontinued therapy in the first trimester, the figure was just under 17%.

“Pregnancy outcomes were within the expected range, but a potential increased risk for small for gestational age newborns justified further investigation,” Dr. Thiel said.
 

Reassuring data

Angie Child Jelin, MD, director of the first trimester screening program and associate professor of gynecology and obstetrics at Johns Hopkins University, Baltimore, said that the increase in the number of pregnant patients with MS seen in their clinic could be caused in part by the growing body of work on MS treatment during pregnancy.

“It’s very reassuring that these data have come out and showed how safe they are generally in pregnancy,” Dr. Jalin said.

Although hematologic abnormalities in newborns are thought to be acute, Dr. Jalin said long-term study is needed to better understand any potential lasting effects from those abnormalities, as well as any effects in SGA newborns.

“Long-term outcomes are very hard to acquire, but ideally you’d want long-term outcomes on all of these measures,” Dr. Jalin said.

Funding for the natalizumab study was not disclosed. The ocrelizumab study was funded by F. Hoffmann–La Roche. Dr. Oreja-Guevara received honoraria for consulting and serving on advisory boards from Biogen Idec, F. Hoffmann–La Roche, Genzyme, Merck, Novartis, and Teva. Dr. Thiel has received speaker honoraria from Bayer Healthcare. Dr. Jalin reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

INDIANAPOLIS – The way Maria C. Garzon, MD, sees it, capillary malformations are often misunderstood. She views them not as a single diagnosis but rather as a variety of conditions that fall under the term capillary malformation.

“The challenge is, we also use that term to describe a diagnosis,” Dr. Garzon, professor of dermatology and pediatrics at Columbia University, New York, said at the annual meeting of the Society for Pediatric Dermatology. “We have imperfect terminology. We use many different terms like capillary nevi and vascular stain. Instead of port wine stain, we now use the term port wine birthmark, and old terms like nevus flammeus are still used. This leads to diagnostic confusion, and it’s a barrier to developing care guidelines.”

Some capillary malformations, she noted, are benign and fade away while others can cause disfigurement or herald significant medical issues.

Histologically, she continued, not all capillary malformations are composed of capillaries. “Some are composed of postcapillary venules,” she said. “There are also mixed type capillary malformations that include lymphatic tissue, and the capillary malformation of capillary malformation-arteriovenous malformation (CM-AVM) syndrome shares histologic features of evolving AVMs as opposed to classic port wine birthmarks.”

The most recent International Society for the Study of Vascular Anomalies Classification of Vascular Anomalies was published in 2018 and is currently being updated. Other proposed clinical classifications have been published, including one that is diagnosis-specific and includes 20 different types of capillary malformations (J Eur Acad Dermatol Venereol. 2015 29[12]:2295-305, Pediatr Dermatol. 2016;33[6]:570-84).

“There are also syndromic classifications. Another question relates to the role of genomics: Are we ready for a classification that’s based purely on genetic variants, or do we need to incorporate it into existing classifications?” Dr. Garzon said. “Novel testing technologies using cell-free DNA and digital droplet PCR may be used in the future to establish diagnoses.” Genetic variants are found within capillary malformations, and they tend to be associated with three major pathways: the RAS-MAPK/ERK pathway, the PI3K/Akt/mTOR pathway, and the G protein pathway.

The type of capillary malformation that dermatologists and pediatricians most commonly see is nevus simplex, which occurs in 20%-82% of neonates. Other terms used include angel’s kiss, stork bite, salmon patch, nevus flammeus simplex, fading vascular stain, medial telangiectatic nevus, and butterfly mark. “It’s important to differentiate this from a port wine birthmark,” Dr. Garzon said. “This can be challenging when the birthmark is a darker red color. I have cared for patients who were initially thought to have nevus simplex and later found to have Sturge-Weber syndrome.”

Typical locations of nevus simplex include the central forehead/glabella, eyelids, the nape of the neck, scalp (parietal and occipital), nose, lip area (including philtrum), and the back (lumbosacral area and upper back). Most lesions fade/disappear without treatment (J Am Acad Dermatol. 2020;63[5]:805-14). Rare genetic syndromes associated with exaggerated nevus simplex complex include macrocephaly-capillary malformation syndrome and Beckwith-Wiedemann syndrome, “which tells us that this is a heterogeneous group of patients,” she said.

Dr. Garzon added that it’s “incredibly common” to see an eczema flare occurring within a nevus simplex on the nape of the neck. These patients will have a patch of atopic dermatitis that doesn’t get better. “Beneath it is their nevus simplex,” she said. “Remind parents that even after treating the eczema, the pink patch is not going to go away” (Pediatr Rep. 2021;13[1]:131-4).

Meanwhile, the classic port wine birthmark is usually congenital, uniform, and darker red in color. It darkens with maturity and the pattern will correlate with embryonic vasculature. “I am very wary of acquired port wine lesions,” she added. “It’s been described with trauma-related lesions, but early morphea can also mimic a port wine birthmark. You will see this if you’re practicing pediatric dermatology.”

Nearly a decade ago researchers established a link between port wine birthmarks and genetic variants in the GNAQ gene. “We see this in GNA11 as well,” Dr. Garzon said. “These changes are found in isolated port wine stains, and in Sturge-Weber syndrome. We now know that GNAQ drives the formation of large blood vessels through angiopoietin-2,” she noted (Arterioscler Throm Vasc Biol. 2022;42[1]:e27-43).

In general, studies that have examined genotype-phenotype correlations have demonstrated that the classic port wine birthmark is associated with GNAQ while GNA11 variants can be associated with a more reticulated pattern. “But this is not as clearcut as it seems,” she said. Investigators of a recent study showed an association between hypertension and renal anomalies in patients with skin capillary malformations and mosaic GNAQ or GNA11 variants. “This is a new finding,” she said. “Investigators are working to understand this association.”

Port wine birthmarks with the highest risk of Sturge-Weber syndrome include those that involve the forehead, upper eyelid, the midline frontonasal area, the hemifacial area, and median sites. “Patients who have this should be evaluated at birth,” Dr. Garzon said. “You should not delay for 2 months. They should be evaluated by ophthalmology and neurology early.”

The other morphologies commonly seen are “geographic” well-demarcated capillary malformations, which are dark in color. These lesions can be seen in conditions that are associated with genetic variants in PIK3CA (PROS) and include classic Klippel-Trenaunay syndrome, CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal) syndrome, and CLAPO (capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry of the face and limbs, and partial or generalized overgrowth) syndrome.

“Reticulated stains are much more heterogeneous,” Dr. Garzon said. “They can be localized or widespread. When you see a patient with a widespread reticulated capillary malformation, think about diffuse capillary malformation with overgrowth (DCMO). This condition is clinically and genetically heterogenous with the affected tissue of some patients showing variants in GNA11 while others have variants in PIK3CA. Therefore, a thorough examination at presentation and long-term follow-up is very important.”

Dr. Garzon disclosed that she is a member of the executive board for the International Society for the Study of Vascular Anomalies.

INDIANAPOLIS – The way Maria C. Garzon, MD, sees it, capillary malformations are often misunderstood. She views them not as a single diagnosis but rather as a variety of conditions that fall under the term capillary malformation.

“The challenge is, we also use that term to describe a diagnosis,” Dr. Garzon, professor of dermatology and pediatrics at Columbia University, New York, said at the annual meeting of the Society for Pediatric Dermatology. “We have imperfect terminology. We use many different terms like capillary nevi and vascular stain. Instead of port wine stain, we now use the term port wine birthmark, and old terms like nevus flammeus are still used. This leads to diagnostic confusion, and it’s a barrier to developing care guidelines.”

Some capillary malformations, she noted, are benign and fade away while others can cause disfigurement or herald significant medical issues.

Histologically, she continued, not all capillary malformations are composed of capillaries. “Some are composed of postcapillary venules,” she said. “There are also mixed type capillary malformations that include lymphatic tissue, and the capillary malformation of capillary malformation-arteriovenous malformation (CM-AVM) syndrome shares histologic features of evolving AVMs as opposed to classic port wine birthmarks.”

The most recent International Society for the Study of Vascular Anomalies Classification of Vascular Anomalies was published in 2018 and is currently being updated. Other proposed clinical classifications have been published, including one that is diagnosis-specific and includes 20 different types of capillary malformations (J Eur Acad Dermatol Venereol. 2015 29[12]:2295-305, Pediatr Dermatol. 2016;33[6]:570-84).

“There are also syndromic classifications. Another question relates to the role of genomics: Are we ready for a classification that’s based purely on genetic variants, or do we need to incorporate it into existing classifications?” Dr. Garzon said. “Novel testing technologies using cell-free DNA and digital droplet PCR may be used in the future to establish diagnoses.” Genetic variants are found within capillary malformations, and they tend to be associated with three major pathways: the RAS-MAPK/ERK pathway, the PI3K/Akt/mTOR pathway, and the G protein pathway.

The type of capillary malformation that dermatologists and pediatricians most commonly see is nevus simplex, which occurs in 20%-82% of neonates. Other terms used include angel’s kiss, stork bite, salmon patch, nevus flammeus simplex, fading vascular stain, medial telangiectatic nevus, and butterfly mark. “It’s important to differentiate this from a port wine birthmark,” Dr. Garzon said. “This can be challenging when the birthmark is a darker red color. I have cared for patients who were initially thought to have nevus simplex and later found to have Sturge-Weber syndrome.”

Typical locations of nevus simplex include the central forehead/glabella, eyelids, the nape of the neck, scalp (parietal and occipital), nose, lip area (including philtrum), and the back (lumbosacral area and upper back). Most lesions fade/disappear without treatment (J Am Acad Dermatol. 2020;63[5]:805-14). Rare genetic syndromes associated with exaggerated nevus simplex complex include macrocephaly-capillary malformation syndrome and Beckwith-Wiedemann syndrome, “which tells us that this is a heterogeneous group of patients,” she said.

Dr. Garzon added that it’s “incredibly common” to see an eczema flare occurring within a nevus simplex on the nape of the neck. These patients will have a patch of atopic dermatitis that doesn’t get better. “Beneath it is their nevus simplex,” she said. “Remind parents that even after treating the eczema, the pink patch is not going to go away” (Pediatr Rep. 2021;13[1]:131-4).

Meanwhile, the classic port wine birthmark is usually congenital, uniform, and darker red in color. It darkens with maturity and the pattern will correlate with embryonic vasculature. “I am very wary of acquired port wine lesions,” she added. “It’s been described with trauma-related lesions, but early morphea can also mimic a port wine birthmark. You will see this if you’re practicing pediatric dermatology.”

Nearly a decade ago researchers established a link between port wine birthmarks and genetic variants in the GNAQ gene. “We see this in GNA11 as well,” Dr. Garzon said. “These changes are found in isolated port wine stains, and in Sturge-Weber syndrome. We now know that GNAQ drives the formation of large blood vessels through angiopoietin-2,” she noted (Arterioscler Throm Vasc Biol. 2022;42[1]:e27-43).

In general, studies that have examined genotype-phenotype correlations have demonstrated that the classic port wine birthmark is associated with GNAQ while GNA11 variants can be associated with a more reticulated pattern. “But this is not as clearcut as it seems,” she said. Investigators of a recent study showed an association between hypertension and renal anomalies in patients with skin capillary malformations and mosaic GNAQ or GNA11 variants. “This is a new finding,” she said. “Investigators are working to understand this association.”

Port wine birthmarks with the highest risk of Sturge-Weber syndrome include those that involve the forehead, upper eyelid, the midline frontonasal area, the hemifacial area, and median sites. “Patients who have this should be evaluated at birth,” Dr. Garzon said. “You should not delay for 2 months. They should be evaluated by ophthalmology and neurology early.”

The other morphologies commonly seen are “geographic” well-demarcated capillary malformations, which are dark in color. These lesions can be seen in conditions that are associated with genetic variants in PIK3CA (PROS) and include classic Klippel-Trenaunay syndrome, CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal) syndrome, and CLAPO (capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry of the face and limbs, and partial or generalized overgrowth) syndrome.

“Reticulated stains are much more heterogeneous,” Dr. Garzon said. “They can be localized or widespread. When you see a patient with a widespread reticulated capillary malformation, think about diffuse capillary malformation with overgrowth (DCMO). This condition is clinically and genetically heterogenous with the affected tissue of some patients showing variants in GNA11 while others have variants in PIK3CA. Therefore, a thorough examination at presentation and long-term follow-up is very important.”

Dr. Garzon disclosed that she is a member of the executive board for the International Society for the Study of Vascular Anomalies.

INDIANAPOLIS – The way Maria C. Garzon, MD, sees it, capillary malformations are often misunderstood. She views them not as a single diagnosis but rather as a variety of conditions that fall under the term capillary malformation.

“The challenge is, we also use that term to describe a diagnosis,” Dr. Garzon, professor of dermatology and pediatrics at Columbia University, New York, said at the annual meeting of the Society for Pediatric Dermatology. “We have imperfect terminology. We use many different terms like capillary nevi and vascular stain. Instead of port wine stain, we now use the term port wine birthmark, and old terms like nevus flammeus are still used. This leads to diagnostic confusion, and it’s a barrier to developing care guidelines.”

Some capillary malformations, she noted, are benign and fade away while others can cause disfigurement or herald significant medical issues.

Histologically, she continued, not all capillary malformations are composed of capillaries. “Some are composed of postcapillary venules,” she said. “There are also mixed type capillary malformations that include lymphatic tissue, and the capillary malformation of capillary malformation-arteriovenous malformation (CM-AVM) syndrome shares histologic features of evolving AVMs as opposed to classic port wine birthmarks.”

The most recent International Society for the Study of Vascular Anomalies Classification of Vascular Anomalies was published in 2018 and is currently being updated. Other proposed clinical classifications have been published, including one that is diagnosis-specific and includes 20 different types of capillary malformations (J Eur Acad Dermatol Venereol. 2015 29[12]:2295-305, Pediatr Dermatol. 2016;33[6]:570-84).

“There are also syndromic classifications. Another question relates to the role of genomics: Are we ready for a classification that’s based purely on genetic variants, or do we need to incorporate it into existing classifications?” Dr. Garzon said. “Novel testing technologies using cell-free DNA and digital droplet PCR may be used in the future to establish diagnoses.” Genetic variants are found within capillary malformations, and they tend to be associated with three major pathways: the RAS-MAPK/ERK pathway, the PI3K/Akt/mTOR pathway, and the G protein pathway.

The type of capillary malformation that dermatologists and pediatricians most commonly see is nevus simplex, which occurs in 20%-82% of neonates. Other terms used include angel’s kiss, stork bite, salmon patch, nevus flammeus simplex, fading vascular stain, medial telangiectatic nevus, and butterfly mark. “It’s important to differentiate this from a port wine birthmark,” Dr. Garzon said. “This can be challenging when the birthmark is a darker red color. I have cared for patients who were initially thought to have nevus simplex and later found to have Sturge-Weber syndrome.”

Typical locations of nevus simplex include the central forehead/glabella, eyelids, the nape of the neck, scalp (parietal and occipital), nose, lip area (including philtrum), and the back (lumbosacral area and upper back). Most lesions fade/disappear without treatment (J Am Acad Dermatol. 2020;63[5]:805-14). Rare genetic syndromes associated with exaggerated nevus simplex complex include macrocephaly-capillary malformation syndrome and Beckwith-Wiedemann syndrome, “which tells us that this is a heterogeneous group of patients,” she said.

Dr. Garzon added that it’s “incredibly common” to see an eczema flare occurring within a nevus simplex on the nape of the neck. These patients will have a patch of atopic dermatitis that doesn’t get better. “Beneath it is their nevus simplex,” she said. “Remind parents that even after treating the eczema, the pink patch is not going to go away” (Pediatr Rep. 2021;13[1]:131-4).

Meanwhile, the classic port wine birthmark is usually congenital, uniform, and darker red in color. It darkens with maturity and the pattern will correlate with embryonic vasculature. “I am very wary of acquired port wine lesions,” she added. “It’s been described with trauma-related lesions, but early morphea can also mimic a port wine birthmark. You will see this if you’re practicing pediatric dermatology.”

Nearly a decade ago researchers established a link between port wine birthmarks and genetic variants in the GNAQ gene. “We see this in GNA11 as well,” Dr. Garzon said. “These changes are found in isolated port wine stains, and in Sturge-Weber syndrome. We now know that GNAQ drives the formation of large blood vessels through angiopoietin-2,” she noted (Arterioscler Throm Vasc Biol. 2022;42[1]:e27-43).

In general, studies that have examined genotype-phenotype correlations have demonstrated that the classic port wine birthmark is associated with GNAQ while GNA11 variants can be associated with a more reticulated pattern. “But this is not as clearcut as it seems,” she said. Investigators of a recent study showed an association between hypertension and renal anomalies in patients with skin capillary malformations and mosaic GNAQ or GNA11 variants. “This is a new finding,” she said. “Investigators are working to understand this association.”

Port wine birthmarks with the highest risk of Sturge-Weber syndrome include those that involve the forehead, upper eyelid, the midline frontonasal area, the hemifacial area, and median sites. “Patients who have this should be evaluated at birth,” Dr. Garzon said. “You should not delay for 2 months. They should be evaluated by ophthalmology and neurology early.”

The other morphologies commonly seen are “geographic” well-demarcated capillary malformations, which are dark in color. These lesions can be seen in conditions that are associated with genetic variants in PIK3CA (PROS) and include classic Klippel-Trenaunay syndrome, CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal) syndrome, and CLAPO (capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry of the face and limbs, and partial or generalized overgrowth) syndrome.

“Reticulated stains are much more heterogeneous,” Dr. Garzon said. “They can be localized or widespread. When you see a patient with a widespread reticulated capillary malformation, think about diffuse capillary malformation with overgrowth (DCMO). This condition is clinically and genetically heterogenous with the affected tissue of some patients showing variants in GNA11 while others have variants in PIK3CA. Therefore, a thorough examination at presentation and long-term follow-up is very important.”

Dr. Garzon disclosed that she is a member of the executive board for the International Society for the Study of Vascular Anomalies.

Drugs commonly used to treat erectile dysfunction (ED) are not associated with a decreased risk of Alzheimer’s disease and related dementias (ADRD), new research shows.

The findings contradict results from a previous study that suggested that individuals who take sildenafil (Viagra) were significantly less likely to develop Alzheimer’s.

The new research, part of a larger effort to identify existing medications that could be repurposed to treat ADRD, employed a study design that reduced the risk for potential bias that may have influenced the earlier findings, the investigators note.

“That study came out last fall and was widely covered in the media, and we thought there were some methodological shortcomings that might have explained the results,” lead investigator Rishi Desai, PhD, assistant professor of medicine at Harvard Medical School and an associate epidemiologist at Brigham and Women’s Hospital, both in Boston, said in an interview.

The new study was published online in Brain Communications.


 

Not the final word?

Animal studies suggest that phosphodiesterase-5 (PDE5) inhibitors, a drug class that includes the ED drugs sildenafil and tadalafil (Cialis), improve memory and cognitive function and reduce amyloid burden. But studies in humans have yielded conflicting results.*

Although the new research and the work published last year both drew on Medicare data, they examined different patient populations.

The first study compared those who took sildenafil for any reason to those who did not take it. That design likely resulted in an analysis of a comparison of individuals with ED – the most common indication for sildenafil – to generally older individuals with diabetes or hypertension, Dr. Desai said.

In contrast, the current study included only those with pulmonary arterial hypertension (PAH), which is also an indication for PDE5 inhibitors. The researchers compared ADRD incidence in those who took PDE5 inhibitors with the incidence among those who took a different medication to treat their PAH. They used propensity matching to create two groups with similar characteristics and examined the data using four analytic strategies.

The investigators found no significant difference between groups in the incidence of ADRD, regardless of the strategy they used. Cell culture studies also revealed no protective effect from PDE5 inhibitors.

“No study of this kind should claim the final word,” Dr. Desai said. “It is extremely difficult to nail down causality from these types of data sources.”
 

Impressive study design

Commenting on the findings, David Knopman, MD, professor of neurology at Mayo Clinic, Rochester, Minn., described the study design as “impressive” for its efforts to minimize bias, a key limitation in the previous study.

“It was always the case that the claims about sildenafil needed further developmental work prior to testing the drug in randomized controlled trials,” Dr. Knopman said. “The evidence for the use of the drug was never sufficient for clinicians to use it in their patients.”

The study was funded by National Institute on Aging. Dr. Desai is an investigator who receives research grants from Bayer, Vertex, and Novartis that were given to the Brigham and Women’s Hospital for unrelated projects. Dr. Knopman has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Correction, 11/3/22: An earlier version of this article misstated the abbreviation for phosphodiesterase-5. It is PDE-5.

Drugs commonly used to treat erectile dysfunction (ED) are not associated with a decreased risk of Alzheimer’s disease and related dementias (ADRD), new research shows.

The findings contradict results from a previous study that suggested that individuals who take sildenafil (Viagra) were significantly less likely to develop Alzheimer’s.

The new research, part of a larger effort to identify existing medications that could be repurposed to treat ADRD, employed a study design that reduced the risk for potential bias that may have influenced the earlier findings, the investigators note.

“That study came out last fall and was widely covered in the media, and we thought there were some methodological shortcomings that might have explained the results,” lead investigator Rishi Desai, PhD, assistant professor of medicine at Harvard Medical School and an associate epidemiologist at Brigham and Women’s Hospital, both in Boston, said in an interview.

The new study was published online in Brain Communications.


 

Not the final word?

Animal studies suggest that phosphodiesterase-5 (PDE5) inhibitors, a drug class that includes the ED drugs sildenafil and tadalafil (Cialis), improve memory and cognitive function and reduce amyloid burden. But studies in humans have yielded conflicting results.*

Although the new research and the work published last year both drew on Medicare data, they examined different patient populations.

The first study compared those who took sildenafil for any reason to those who did not take it. That design likely resulted in an analysis of a comparison of individuals with ED – the most common indication for sildenafil – to generally older individuals with diabetes or hypertension, Dr. Desai said.

In contrast, the current study included only those with pulmonary arterial hypertension (PAH), which is also an indication for PDE5 inhibitors. The researchers compared ADRD incidence in those who took PDE5 inhibitors with the incidence among those who took a different medication to treat their PAH. They used propensity matching to create two groups with similar characteristics and examined the data using four analytic strategies.

The investigators found no significant difference between groups in the incidence of ADRD, regardless of the strategy they used. Cell culture studies also revealed no protective effect from PDE5 inhibitors.

“No study of this kind should claim the final word,” Dr. Desai said. “It is extremely difficult to nail down causality from these types of data sources.”
 

Impressive study design

Commenting on the findings, David Knopman, MD, professor of neurology at Mayo Clinic, Rochester, Minn., described the study design as “impressive” for its efforts to minimize bias, a key limitation in the previous study.

“It was always the case that the claims about sildenafil needed further developmental work prior to testing the drug in randomized controlled trials,” Dr. Knopman said. “The evidence for the use of the drug was never sufficient for clinicians to use it in their patients.”

The study was funded by National Institute on Aging. Dr. Desai is an investigator who receives research grants from Bayer, Vertex, and Novartis that were given to the Brigham and Women’s Hospital for unrelated projects. Dr. Knopman has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Correction, 11/3/22: An earlier version of this article misstated the abbreviation for phosphodiesterase-5. It is PDE-5.

Drugs commonly used to treat erectile dysfunction (ED) are not associated with a decreased risk of Alzheimer’s disease and related dementias (ADRD), new research shows.

The findings contradict results from a previous study that suggested that individuals who take sildenafil (Viagra) were significantly less likely to develop Alzheimer’s.

The new research, part of a larger effort to identify existing medications that could be repurposed to treat ADRD, employed a study design that reduced the risk for potential bias that may have influenced the earlier findings, the investigators note.

“That study came out last fall and was widely covered in the media, and we thought there were some methodological shortcomings that might have explained the results,” lead investigator Rishi Desai, PhD, assistant professor of medicine at Harvard Medical School and an associate epidemiologist at Brigham and Women’s Hospital, both in Boston, said in an interview.

The new study was published online in Brain Communications.


 

Not the final word?

Animal studies suggest that phosphodiesterase-5 (PDE5) inhibitors, a drug class that includes the ED drugs sildenafil and tadalafil (Cialis), improve memory and cognitive function and reduce amyloid burden. But studies in humans have yielded conflicting results.*

Although the new research and the work published last year both drew on Medicare data, they examined different patient populations.

The first study compared those who took sildenafil for any reason to those who did not take it. That design likely resulted in an analysis of a comparison of individuals with ED – the most common indication for sildenafil – to generally older individuals with diabetes or hypertension, Dr. Desai said.

In contrast, the current study included only those with pulmonary arterial hypertension (PAH), which is also an indication for PDE5 inhibitors. The researchers compared ADRD incidence in those who took PDE5 inhibitors with the incidence among those who took a different medication to treat their PAH. They used propensity matching to create two groups with similar characteristics and examined the data using four analytic strategies.

The investigators found no significant difference between groups in the incidence of ADRD, regardless of the strategy they used. Cell culture studies also revealed no protective effect from PDE5 inhibitors.

“No study of this kind should claim the final word,” Dr. Desai said. “It is extremely difficult to nail down causality from these types of data sources.”
 

Impressive study design

Commenting on the findings, David Knopman, MD, professor of neurology at Mayo Clinic, Rochester, Minn., described the study design as “impressive” for its efforts to minimize bias, a key limitation in the previous study.

“It was always the case that the claims about sildenafil needed further developmental work prior to testing the drug in randomized controlled trials,” Dr. Knopman said. “The evidence for the use of the drug was never sufficient for clinicians to use it in their patients.”

The study was funded by National Institute on Aging. Dr. Desai is an investigator who receives research grants from Bayer, Vertex, and Novartis that were given to the Brigham and Women’s Hospital for unrelated projects. Dr. Knopman has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Correction, 11/3/22: An earlier version of this article misstated the abbreviation for phosphodiesterase-5. It is PDE-5.

Listening to birdsong appears to have a positive and significant impact on mental health and mood, new research suggests.

Investigators found that people who listened to recordings of birds singing experienced a significant reduction in anxiety and paranoia. In contrast, the researchers also found that recordings of traffic noises, including car engines, sirens, and construction, increased depressive states.

“The results suggest that it may be worthwhile to investigate the targeted use of natural sounds such as birdsong in a clinical setting – for example, in hospital waiting rooms or in psychiatric settings,” study investigator Emil Stobbe, MSc, a predoctoral fellow at the Max Planck Institute for Human Development, Berlin, said in an interview.

“If someone is seeking an easily accessible intervention to lower distress, listening to an audio clip of birds singing might be a great option,” he added.

The study was published online in Scientific Reports.
 

Nature’s calming effect

The aim of the research was “to investigate how the physical environment impact brain and mental health,” Mr. Stobbe said.

Mr. Stobbe said that there is significantly more research examining visual properties of the physical environment but that the auditory domain is not as well researched, although, he added, that the beneficial effects of interactions with nature are “well studied.”

He noted that anxiety and paranoia can be experienced by many individuals even though they may be unaware that they are experiencing these states.

“We wanted to investigate if the beneficial effects of nature can also exert their impact on these states. In theory, birds can be representational for natural and vital environment, which, in turn, transfer the positive effects of nature on birdsong listeners,” he said.

A previous study compared nature versus city soundscape conditions and showed that the nature soundscape improved participants’ cognitive performance but did not improve mood. The present study added diversity to the soundscapes and focused not only on cognition and general mood but also on state paranoia, “which can be measured in a change-sensitive manner” and “has been shown to increase in response to traffic noise.”

The researchers hypothesized that birdsong would have a greater beneficial effect on mood and paranoia and on cognitive performance compared with traffic noise. They also investigated whether greater versus lower diversity of bird species or noise sources within the soundscapes “would be a relevant factor modulating the effects.”

The researchers recruited participants (n = 295) from a crowdsourcing platform. Participants’ mean age was late 20s (standard deviations ranged from 6.30 to 7.72), with a greater proportion of male versus female participants.

To be included, participants were required to have no history of mental illness, hearing difficulties, substance/drug intake, or suicidal thoughts/tendencies.

The outcomes of interest (mood, paranoia, cognitive performance) were measured before and after soundscape exposure and each soundscape had a low- versus high-diversity version. This resulted in several analyses that compared two types of sounds (birdsongs vs. traffic noise) x two levels of diversity (low vs. high diversity) and two time points (pre- vs. post exposure).

The exposure to sounds lasted for 6 minutes, after which they were asked to report (on a 0-100 visual scale) how diverse/monotone, beautiful, and pleasant they perceived the soundscape to be.
 

Reduction in depressive symptoms

Participants were divided into four groups: low-diversity traffic noise soundscape (n = 83), high-diversity traffic noise soundscape (n = 60), low-diversity birdsong soundscape (n = 63), and high-diversity birdsong soundscape (n = 80)

In addition to listening to the sounds, participants completed questionnaires measuring mood (depression and anxiety) and paranoia as well as a test of digit span cognitive performance (both the forward and the backward versions).

The type, diversity, and type x diversity all revealed significant effect sizes (F[3, 276] = 78.6; P < .001; eta-squared = 0.461; F[3, 276] = 3.16; P = .025; eta-squared = 0.033; and F[3, 276] = 2.66; P = .028, respectively), “suggesting that all of these factors, as well as their interaction, had a significant impact on the perception of soundscapes (that is, ratings on monotony/diversity, beauty, and pleasantness).”

A post hoc examination showed that depressive symptoms significantly increased within the low- and high-diversity urban soundscapes but decreased significantly in the high-diversity birdsong soundscapes (T[1, 60] = –2.57; P = .012; d = –0.29).

For anxiety, the post hoc within-group analyses found no effects within low- and high-diversity traffic noise conditions (T[1, 82] = –1.37; P = .174; d = –0.15 and T[1, 68] = 0.49; P = .629; d = 0.06, respectively). By contrast, there were significant declines in both birdsong conditions (low diversity: T[1, 62] = –6.13; P < .001; d = –0.77; high diversity: T[1, 60] = –6.32; P < .001; d =  –0.70).

Similarly, there were no changes in participants with paranoia when they listened to either low- or high-diversity traffic noises (T[1, 82] = –0.55; P = .583; d = –0.06 and T[1, 68] = 0.67; P = .507; d = 0.08, respectively). On the other hand, both birdsong conditions yielded reductions in paranoia (low diversity: T[1, 62] = –5.90; P < .001; d = –0.74; high diversity: T[1, 60] =  –4.11; P < .001; d = –0.46).

None of the soundscapes had any effect on cognition.

“In theory, birds can be representational for natural and vital environments which, in turn, transfer the positive effects of nature on birdsong listeners,” said Mr. Stobbe.

“Taken together, the findings of the current study provide another facet of why interactions with nature can be beneficial for our mental health, and it is highly important to preserve nature,” he added.

Mr. Stobbe said that future research should focus on investigating mixed soundscapes including examining whether the presence of natural sounds in urban settings lower stressors such as traffic noise.
 

An understudied area

Commenting for this article, Ken Duckworth, MD, chief medical officer of the National Alliance on Mental Illness called the study “interesting but limited.”

Dr. Duckworth, who was not involved in the research said that the “benefits of nature are understudied” and agreed with the investigators that it is potentially important to study the use of birdsongs in psychiatric facilities. “Future studies could also correlate the role of birdsong with the mental health benefits/aspects of ‘being in nature,’ which has been found to have some effect.”

Open Access funding was enabled and organized by Projekt DEAL. The authors and Dr. Duckworth declared no competing interests.

A version of this article first appeared on Medscape.com.

Listening to birdsong appears to have a positive and significant impact on mental health and mood, new research suggests.

Investigators found that people who listened to recordings of birds singing experienced a significant reduction in anxiety and paranoia. In contrast, the researchers also found that recordings of traffic noises, including car engines, sirens, and construction, increased depressive states.

“The results suggest that it may be worthwhile to investigate the targeted use of natural sounds such as birdsong in a clinical setting – for example, in hospital waiting rooms or in psychiatric settings,” study investigator Emil Stobbe, MSc, a predoctoral fellow at the Max Planck Institute for Human Development, Berlin, said in an interview.

“If someone is seeking an easily accessible intervention to lower distress, listening to an audio clip of birds singing might be a great option,” he added.

The study was published online in Scientific Reports.
 

Nature’s calming effect

The aim of the research was “to investigate how the physical environment impact brain and mental health,” Mr. Stobbe said.

Mr. Stobbe said that there is significantly more research examining visual properties of the physical environment but that the auditory domain is not as well researched, although, he added, that the beneficial effects of interactions with nature are “well studied.”

He noted that anxiety and paranoia can be experienced by many individuals even though they may be unaware that they are experiencing these states.

“We wanted to investigate if the beneficial effects of nature can also exert their impact on these states. In theory, birds can be representational for natural and vital environment, which, in turn, transfer the positive effects of nature on birdsong listeners,” he said.

A previous study compared nature versus city soundscape conditions and showed that the nature soundscape improved participants’ cognitive performance but did not improve mood. The present study added diversity to the soundscapes and focused not only on cognition and general mood but also on state paranoia, “which can be measured in a change-sensitive manner” and “has been shown to increase in response to traffic noise.”

The researchers hypothesized that birdsong would have a greater beneficial effect on mood and paranoia and on cognitive performance compared with traffic noise. They also investigated whether greater versus lower diversity of bird species or noise sources within the soundscapes “would be a relevant factor modulating the effects.”

The researchers recruited participants (n = 295) from a crowdsourcing platform. Participants’ mean age was late 20s (standard deviations ranged from 6.30 to 7.72), with a greater proportion of male versus female participants.

To be included, participants were required to have no history of mental illness, hearing difficulties, substance/drug intake, or suicidal thoughts/tendencies.

The outcomes of interest (mood, paranoia, cognitive performance) were measured before and after soundscape exposure and each soundscape had a low- versus high-diversity version. This resulted in several analyses that compared two types of sounds (birdsongs vs. traffic noise) x two levels of diversity (low vs. high diversity) and two time points (pre- vs. post exposure).

The exposure to sounds lasted for 6 minutes, after which they were asked to report (on a 0-100 visual scale) how diverse/monotone, beautiful, and pleasant they perceived the soundscape to be.
 

Reduction in depressive symptoms

Participants were divided into four groups: low-diversity traffic noise soundscape (n = 83), high-diversity traffic noise soundscape (n = 60), low-diversity birdsong soundscape (n = 63), and high-diversity birdsong soundscape (n = 80)

In addition to listening to the sounds, participants completed questionnaires measuring mood (depression and anxiety) and paranoia as well as a test of digit span cognitive performance (both the forward and the backward versions).

The type, diversity, and type x diversity all revealed significant effect sizes (F[3, 276] = 78.6; P < .001; eta-squared = 0.461; F[3, 276] = 3.16; P = .025; eta-squared = 0.033; and F[3, 276] = 2.66; P = .028, respectively), “suggesting that all of these factors, as well as their interaction, had a significant impact on the perception of soundscapes (that is, ratings on monotony/diversity, beauty, and pleasantness).”

A post hoc examination showed that depressive symptoms significantly increased within the low- and high-diversity urban soundscapes but decreased significantly in the high-diversity birdsong soundscapes (T[1, 60] = –2.57; P = .012; d = –0.29).

For anxiety, the post hoc within-group analyses found no effects within low- and high-diversity traffic noise conditions (T[1, 82] = –1.37; P = .174; d = –0.15 and T[1, 68] = 0.49; P = .629; d = 0.06, respectively). By contrast, there were significant declines in both birdsong conditions (low diversity: T[1, 62] = –6.13; P < .001; d = –0.77; high diversity: T[1, 60] = –6.32; P < .001; d =  –0.70).

Similarly, there were no changes in participants with paranoia when they listened to either low- or high-diversity traffic noises (T[1, 82] = –0.55; P = .583; d = –0.06 and T[1, 68] = 0.67; P = .507; d = 0.08, respectively). On the other hand, both birdsong conditions yielded reductions in paranoia (low diversity: T[1, 62] = –5.90; P < .001; d = –0.74; high diversity: T[1, 60] =  –4.11; P < .001; d = –0.46).

None of the soundscapes had any effect on cognition.

“In theory, birds can be representational for natural and vital environments which, in turn, transfer the positive effects of nature on birdsong listeners,” said Mr. Stobbe.

“Taken together, the findings of the current study provide another facet of why interactions with nature can be beneficial for our mental health, and it is highly important to preserve nature,” he added.

Mr. Stobbe said that future research should focus on investigating mixed soundscapes including examining whether the presence of natural sounds in urban settings lower stressors such as traffic noise.
 

An understudied area

Commenting for this article, Ken Duckworth, MD, chief medical officer of the National Alliance on Mental Illness called the study “interesting but limited.”

Dr. Duckworth, who was not involved in the research said that the “benefits of nature are understudied” and agreed with the investigators that it is potentially important to study the use of birdsongs in psychiatric facilities. “Future studies could also correlate the role of birdsong with the mental health benefits/aspects of ‘being in nature,’ which has been found to have some effect.”

Open Access funding was enabled and organized by Projekt DEAL. The authors and Dr. Duckworth declared no competing interests.

A version of this article first appeared on Medscape.com.

Listening to birdsong appears to have a positive and significant impact on mental health and mood, new research suggests.

Investigators found that people who listened to recordings of birds singing experienced a significant reduction in anxiety and paranoia. In contrast, the researchers also found that recordings of traffic noises, including car engines, sirens, and construction, increased depressive states.

“The results suggest that it may be worthwhile to investigate the targeted use of natural sounds such as birdsong in a clinical setting – for example, in hospital waiting rooms or in psychiatric settings,” study investigator Emil Stobbe, MSc, a predoctoral fellow at the Max Planck Institute for Human Development, Berlin, said in an interview.

“If someone is seeking an easily accessible intervention to lower distress, listening to an audio clip of birds singing might be a great option,” he added.

The study was published online in Scientific Reports.
 

Nature’s calming effect

The aim of the research was “to investigate how the physical environment impact brain and mental health,” Mr. Stobbe said.

Mr. Stobbe said that there is significantly more research examining visual properties of the physical environment but that the auditory domain is not as well researched, although, he added, that the beneficial effects of interactions with nature are “well studied.”

He noted that anxiety and paranoia can be experienced by many individuals even though they may be unaware that they are experiencing these states.

“We wanted to investigate if the beneficial effects of nature can also exert their impact on these states. In theory, birds can be representational for natural and vital environment, which, in turn, transfer the positive effects of nature on birdsong listeners,” he said.

A previous study compared nature versus city soundscape conditions and showed that the nature soundscape improved participants’ cognitive performance but did not improve mood. The present study added diversity to the soundscapes and focused not only on cognition and general mood but also on state paranoia, “which can be measured in a change-sensitive manner” and “has been shown to increase in response to traffic noise.”

The researchers hypothesized that birdsong would have a greater beneficial effect on mood and paranoia and on cognitive performance compared with traffic noise. They also investigated whether greater versus lower diversity of bird species or noise sources within the soundscapes “would be a relevant factor modulating the effects.”

The researchers recruited participants (n = 295) from a crowdsourcing platform. Participants’ mean age was late 20s (standard deviations ranged from 6.30 to 7.72), with a greater proportion of male versus female participants.

To be included, participants were required to have no history of mental illness, hearing difficulties, substance/drug intake, or suicidal thoughts/tendencies.

The outcomes of interest (mood, paranoia, cognitive performance) were measured before and after soundscape exposure and each soundscape had a low- versus high-diversity version. This resulted in several analyses that compared two types of sounds (birdsongs vs. traffic noise) x two levels of diversity (low vs. high diversity) and two time points (pre- vs. post exposure).

The exposure to sounds lasted for 6 minutes, after which they were asked to report (on a 0-100 visual scale) how diverse/monotone, beautiful, and pleasant they perceived the soundscape to be.
 

Reduction in depressive symptoms

Participants were divided into four groups: low-diversity traffic noise soundscape (n = 83), high-diversity traffic noise soundscape (n = 60), low-diversity birdsong soundscape (n = 63), and high-diversity birdsong soundscape (n = 80)

In addition to listening to the sounds, participants completed questionnaires measuring mood (depression and anxiety) and paranoia as well as a test of digit span cognitive performance (both the forward and the backward versions).

The type, diversity, and type x diversity all revealed significant effect sizes (F[3, 276] = 78.6; P < .001; eta-squared = 0.461; F[3, 276] = 3.16; P = .025; eta-squared = 0.033; and F[3, 276] = 2.66; P = .028, respectively), “suggesting that all of these factors, as well as their interaction, had a significant impact on the perception of soundscapes (that is, ratings on monotony/diversity, beauty, and pleasantness).”

A post hoc examination showed that depressive symptoms significantly increased within the low- and high-diversity urban soundscapes but decreased significantly in the high-diversity birdsong soundscapes (T[1, 60] = –2.57; P = .012; d = –0.29).

For anxiety, the post hoc within-group analyses found no effects within low- and high-diversity traffic noise conditions (T[1, 82] = –1.37; P = .174; d = –0.15 and T[1, 68] = 0.49; P = .629; d = 0.06, respectively). By contrast, there were significant declines in both birdsong conditions (low diversity: T[1, 62] = –6.13; P < .001; d = –0.77; high diversity: T[1, 60] = –6.32; P < .001; d =  –0.70).

Similarly, there were no changes in participants with paranoia when they listened to either low- or high-diversity traffic noises (T[1, 82] = –0.55; P = .583; d = –0.06 and T[1, 68] = 0.67; P = .507; d = 0.08, respectively). On the other hand, both birdsong conditions yielded reductions in paranoia (low diversity: T[1, 62] = –5.90; P < .001; d = –0.74; high diversity: T[1, 60] =  –4.11; P < .001; d = –0.46).

None of the soundscapes had any effect on cognition.

“In theory, birds can be representational for natural and vital environments which, in turn, transfer the positive effects of nature on birdsong listeners,” said Mr. Stobbe.

“Taken together, the findings of the current study provide another facet of why interactions with nature can be beneficial for our mental health, and it is highly important to preserve nature,” he added.

Mr. Stobbe said that future research should focus on investigating mixed soundscapes including examining whether the presence of natural sounds in urban settings lower stressors such as traffic noise.
 

An understudied area

Commenting for this article, Ken Duckworth, MD, chief medical officer of the National Alliance on Mental Illness called the study “interesting but limited.”

Dr. Duckworth, who was not involved in the research said that the “benefits of nature are understudied” and agreed with the investigators that it is potentially important to study the use of birdsongs in psychiatric facilities. “Future studies could also correlate the role of birdsong with the mental health benefits/aspects of ‘being in nature,’ which has been found to have some effect.”

Open Access funding was enabled and organized by Projekt DEAL. The authors and Dr. Duckworth declared no competing interests.

A version of this article first appeared on Medscape.com.

One in 5. It almost seems unimaginable that this is the real number of people who are struggling with long COVID, especially considering how many people in the United States have had COVID-19 at this point (more than 96 million). Yet I continue to hear of people who are struggling, and we continue to see a flood of people in the long COVID clinic. It isn’t over, and long COVID is the new pandemic.

Even more unimaginable at this time is that it’s happening to me. I’ve experienced not only the disabling effects of long COVID, but I’ve also seen, firsthand, the frustration of navigating diagnosis and treatment. It’s given me a taste of what millions of other patients are going through.
 

Vaxxed, masked, and (too) relaxed

I caught COVID-19 (probably Omicron BA.5) that presented as sniffles, making me think it was probably just allergies. However, my resting heart rate was up on my Garmin watch, so of course I got tested and was positive.

With my symptoms virtually nonexistent, it seemed, at the time, merely an inconvenience, because I was forced to isolate away from family and friends, who all stayed negative.

But 2 weeks later, I began to have urticaria – hives – after physical exertion. Did that mean my mast cells were angry? There’s some evidence these immune cells become overactivated in some patients with COVID. Next, I began to experience lightheadedness and the rapid heartbeat of tachycardia. The tachycardia was especially bad any time I physically exerted myself, including on a walk. Imagine me – a lover of all bargain shopping – cutting short a trip to the outlet mall on a particularly bad day when my heart rate was 140 after taking just a few steps. This was orthostatic intolerance.

Then came the severe worsening of my migraines – which are often vestibular, making me nauseated and dizzy on top of the throbbing.

I was of course familiar with these symptoms, as professor and chair of the department of rehabilitation medicine at the Joe R. and Teresa Lozano Long School of Medicine at University of Texas Health Science Center, San Antonio. I developed a post-COVID recovery clinic to help patients.

So I knew about postexertional malaise (PEM) and postexertional symptom exacerbation (PESE), but I was now experiencing these distressing symptoms firsthand.

Clinicians really need to look for this cardinal sign of long COVID as well as evidence of myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). ME/CFS is marked by exacerbation of fatigue or symptoms after an activity that could previously be done without these aftereffects. In my case, as an All-American Masters miler with several marathons under my belt, running 5 miles is a walk in the park. But now, I pay for those 5 miles for the rest of the day on the couch or with palpitations, dizziness, and fatigue the following day. Busy clinic day full of procedures? I would have to be sitting by the end of it. Bed by 9 PM was not always early enough.
 

Becoming a statistic

Here I am, one of the leading experts in the country on caring for people with long COVID, featured in the national news and having testified in front of Congress, and now I am part of that lived experience. Me – a healthy athlete, with no comorbidities, a normal BMI, vaccinated and boosted, and after an almost asymptomatic bout of COVID-19, a victim to long COVID.

You just never know how your body is going to react. Neuroinflammation occurred in studies with mice with mild respiratory COVID and could be happening to me. I did not want a chronic immune-mediated vasculopathy.

So, I did what any other hyperaware physician-researcher would do. I enrolled in the RECOVER trial – a study my own institution is taking part in and one that I recommend to my own patients.

I also decided that I need to access care and not just ignore my symptoms or try to treat them myself.

That’s when things got difficult. There was a wait of at least a month to see my primary care provider – but I was able to use my privileged position as a physician to get in sooner.

My provider said that she had limited knowledge of long COVID, and she hesitated to order some of the tests and treatments that I recommended because they were not yet considered standard of care. I can understand the hesitation. It is engrained in medical education to follow evidence based on the highest-quality research studies. We are slowly learning more about long COVID, but acknowledging the learning curve offers little to patients who need help now.

This has made me realize that we cannot wait on an evidence-based approach – which can take decades to develop – while people are suffering. And it’s important that everyone on the front line learn about some of the manifestations and disease management of long COVID.

I left this first physician visit feeling more defeated than anything and decided to try to push through. That, I quickly realized, was not the right thing to do.

So again, after a couple of significant crashes and days of severe migraines, I phoned a friend: Ratna Bhavaraju-Sanka, MD, the amazing neurologist who treats patients with long COVID alongside me. She squeezed me in on a non-clinic day. Again, I had the privilege to see a specialist most people wait half a year to see. I was diagnosed with both autonomic dysfunction and intractable migraine.

She ordered some intravenous fluids and IV magnesium that would probably help both. But then another obstacle arose. My institution’s infusion center is focused on patients with cancer, and I was unable to schedule treatments there.

Luckily, I knew about the concierge mobile IV hydration therapy companies that come to your house – mostly offering a hangover treatment service. And I am thankful that I had the health literacy and financial ability to pay for some fluids at home.

On another particularly bad day, I phoned other friends – higher-ups at the hospital – who expedited a slot at the hospital infusion center and approval for the IV magnesium.

Thanks to my access, knowledge, and other privileges, I got fairly quick if imperfect care, enrolled in a research trial, and received medications. I knew to pace myself. The vast majority of others with long COVID lack these advantages.
 

The patient with long COVID

Things I have learned that others can learn, too:

• Acknowledge and recognize that long COVID is a disease that is affecting 1 in 5 Americans who catch COVID. Many look completely “normal on the outside.” Please listen to your patients.
• Autonomic dysfunction is a common manifestation of long COVID. A 10-minute stand test goes a long way in diagnosing this condition, from the American Academy of Physical Medicine and Rehabilitation. It is not just anxiety.
• “That’s only in research” is dismissive and harmful. Think outside the box. Follow guidelines. Consider encouraging patients to sign up for trials.
• Screen for PEM/PESE and teach your patients to pace themselves, because pushing through it or doing graded exercises will be harmful.
• We need to train more physicians to treat postacute sequelae of SARS-CoV-2 infection () and other postinfectious conditions, such as ME/CFS.

If long COVID is hard for physicians to understand and deal with, imagine how difficult it is for patients with no expertise in this area.

It is exponentially harder for those with fewer resources, time, and health literacy. My lived experience with long COVID has shown me that being a patient is never easy. You put your body and fate into the hands of trusted professionals and expect validation and assistance, not gaslighting or gatekeeping.

Along with millions of others, I am tired of waiting.

Dr. Gutierrez is Professor and Distinguished Chair, department of rehabilitation medicine, University of Texas Health Science Center at San Antonio. She reported receiving honoraria for lecturing on long COVID and receiving a research grant from Co-PI for the NIH RECOVER trial.

A version of this article first appeared on Medscape.com.

One in 5. It almost seems unimaginable that this is the real number of people who are struggling with long COVID, especially considering how many people in the United States have had COVID-19 at this point (more than 96 million). Yet I continue to hear of people who are struggling, and we continue to see a flood of people in the long COVID clinic. It isn’t over, and long COVID is the new pandemic.

Even more unimaginable at this time is that it’s happening to me. I’ve experienced not only the disabling effects of long COVID, but I’ve also seen, firsthand, the frustration of navigating diagnosis and treatment. It’s given me a taste of what millions of other patients are going through.
 

Vaxxed, masked, and (too) relaxed

I caught COVID-19 (probably Omicron BA.5) that presented as sniffles, making me think it was probably just allergies. However, my resting heart rate was up on my Garmin watch, so of course I got tested and was positive.

With my symptoms virtually nonexistent, it seemed, at the time, merely an inconvenience, because I was forced to isolate away from family and friends, who all stayed negative.

But 2 weeks later, I began to have urticaria – hives – after physical exertion. Did that mean my mast cells were angry? There’s some evidence these immune cells become overactivated in some patients with COVID. Next, I began to experience lightheadedness and the rapid heartbeat of tachycardia. The tachycardia was especially bad any time I physically exerted myself, including on a walk. Imagine me – a lover of all bargain shopping – cutting short a trip to the outlet mall on a particularly bad day when my heart rate was 140 after taking just a few steps. This was orthostatic intolerance.

Then came the severe worsening of my migraines – which are often vestibular, making me nauseated and dizzy on top of the throbbing.

I was of course familiar with these symptoms, as professor and chair of the department of rehabilitation medicine at the Joe R. and Teresa Lozano Long School of Medicine at University of Texas Health Science Center, San Antonio. I developed a post-COVID recovery clinic to help patients.

So I knew about postexertional malaise (PEM) and postexertional symptom exacerbation (PESE), but I was now experiencing these distressing symptoms firsthand.

Clinicians really need to look for this cardinal sign of long COVID as well as evidence of myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). ME/CFS is marked by exacerbation of fatigue or symptoms after an activity that could previously be done without these aftereffects. In my case, as an All-American Masters miler with several marathons under my belt, running 5 miles is a walk in the park. But now, I pay for those 5 miles for the rest of the day on the couch or with palpitations, dizziness, and fatigue the following day. Busy clinic day full of procedures? I would have to be sitting by the end of it. Bed by 9 PM was not always early enough.
 

Becoming a statistic

Here I am, one of the leading experts in the country on caring for people with long COVID, featured in the national news and having testified in front of Congress, and now I am part of that lived experience. Me – a healthy athlete, with no comorbidities, a normal BMI, vaccinated and boosted, and after an almost asymptomatic bout of COVID-19, a victim to long COVID.

You just never know how your body is going to react. Neuroinflammation occurred in studies with mice with mild respiratory COVID and could be happening to me. I did not want a chronic immune-mediated vasculopathy.

So, I did what any other hyperaware physician-researcher would do. I enrolled in the RECOVER trial – a study my own institution is taking part in and one that I recommend to my own patients.

I also decided that I need to access care and not just ignore my symptoms or try to treat them myself.

That’s when things got difficult. There was a wait of at least a month to see my primary care provider – but I was able to use my privileged position as a physician to get in sooner.

My provider said that she had limited knowledge of long COVID, and she hesitated to order some of the tests and treatments that I recommended because they were not yet considered standard of care. I can understand the hesitation. It is engrained in medical education to follow evidence based on the highest-quality research studies. We are slowly learning more about long COVID, but acknowledging the learning curve offers little to patients who need help now.

This has made me realize that we cannot wait on an evidence-based approach – which can take decades to develop – while people are suffering. And it’s important that everyone on the front line learn about some of the manifestations and disease management of long COVID.

I left this first physician visit feeling more defeated than anything and decided to try to push through. That, I quickly realized, was not the right thing to do.

So again, after a couple of significant crashes and days of severe migraines, I phoned a friend: Ratna Bhavaraju-Sanka, MD, the amazing neurologist who treats patients with long COVID alongside me. She squeezed me in on a non-clinic day. Again, I had the privilege to see a specialist most people wait half a year to see. I was diagnosed with both autonomic dysfunction and intractable migraine.

She ordered some intravenous fluids and IV magnesium that would probably help both. But then another obstacle arose. My institution’s infusion center is focused on patients with cancer, and I was unable to schedule treatments there.

Luckily, I knew about the concierge mobile IV hydration therapy companies that come to your house – mostly offering a hangover treatment service. And I am thankful that I had the health literacy and financial ability to pay for some fluids at home.

On another particularly bad day, I phoned other friends – higher-ups at the hospital – who expedited a slot at the hospital infusion center and approval for the IV magnesium.

Thanks to my access, knowledge, and other privileges, I got fairly quick if imperfect care, enrolled in a research trial, and received medications. I knew to pace myself. The vast majority of others with long COVID lack these advantages.
 

The patient with long COVID

Things I have learned that others can learn, too:

• Acknowledge and recognize that long COVID is a disease that is affecting 1 in 5 Americans who catch COVID. Many look completely “normal on the outside.” Please listen to your patients.
• Autonomic dysfunction is a common manifestation of long COVID. A 10-minute stand test goes a long way in diagnosing this condition, from the American Academy of Physical Medicine and Rehabilitation. It is not just anxiety.
• “That’s only in research” is dismissive and harmful. Think outside the box. Follow guidelines. Consider encouraging patients to sign up for trials.
• Screen for PEM/PESE and teach your patients to pace themselves, because pushing through it or doing graded exercises will be harmful.
• We need to train more physicians to treat postacute sequelae of SARS-CoV-2 infection () and other postinfectious conditions, such as ME/CFS.

If long COVID is hard for physicians to understand and deal with, imagine how difficult it is for patients with no expertise in this area.

It is exponentially harder for those with fewer resources, time, and health literacy. My lived experience with long COVID has shown me that being a patient is never easy. You put your body and fate into the hands of trusted professionals and expect validation and assistance, not gaslighting or gatekeeping.

Along with millions of others, I am tired of waiting.

Dr. Gutierrez is Professor and Distinguished Chair, department of rehabilitation medicine, University of Texas Health Science Center at San Antonio. She reported receiving honoraria for lecturing on long COVID and receiving a research grant from Co-PI for the NIH RECOVER trial.

A version of this article first appeared on Medscape.com.

One in 5. It almost seems unimaginable that this is the real number of people who are struggling with long COVID, especially considering how many people in the United States have had COVID-19 at this point (more than 96 million). Yet I continue to hear of people who are struggling, and we continue to see a flood of people in the long COVID clinic. It isn’t over, and long COVID is the new pandemic.

Even more unimaginable at this time is that it’s happening to me. I’ve experienced not only the disabling effects of long COVID, but I’ve also seen, firsthand, the frustration of navigating diagnosis and treatment. It’s given me a taste of what millions of other patients are going through.
 

Vaxxed, masked, and (too) relaxed

I caught COVID-19 (probably Omicron BA.5) that presented as sniffles, making me think it was probably just allergies. However, my resting heart rate was up on my Garmin watch, so of course I got tested and was positive.

With my symptoms virtually nonexistent, it seemed, at the time, merely an inconvenience, because I was forced to isolate away from family and friends, who all stayed negative.

But 2 weeks later, I began to have urticaria – hives – after physical exertion. Did that mean my mast cells were angry? There’s some evidence these immune cells become overactivated in some patients with COVID. Next, I began to experience lightheadedness and the rapid heartbeat of tachycardia. The tachycardia was especially bad any time I physically exerted myself, including on a walk. Imagine me – a lover of all bargain shopping – cutting short a trip to the outlet mall on a particularly bad day when my heart rate was 140 after taking just a few steps. This was orthostatic intolerance.

Then came the severe worsening of my migraines – which are often vestibular, making me nauseated and dizzy on top of the throbbing.

I was of course familiar with these symptoms, as professor and chair of the department of rehabilitation medicine at the Joe R. and Teresa Lozano Long School of Medicine at University of Texas Health Science Center, San Antonio. I developed a post-COVID recovery clinic to help patients.

So I knew about postexertional malaise (PEM) and postexertional symptom exacerbation (PESE), but I was now experiencing these distressing symptoms firsthand.

Clinicians really need to look for this cardinal sign of long COVID as well as evidence of myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). ME/CFS is marked by exacerbation of fatigue or symptoms after an activity that could previously be done without these aftereffects. In my case, as an All-American Masters miler with several marathons under my belt, running 5 miles is a walk in the park. But now, I pay for those 5 miles for the rest of the day on the couch or with palpitations, dizziness, and fatigue the following day. Busy clinic day full of procedures? I would have to be sitting by the end of it. Bed by 9 PM was not always early enough.
 

Becoming a statistic

Here I am, one of the leading experts in the country on caring for people with long COVID, featured in the national news and having testified in front of Congress, and now I am part of that lived experience. Me – a healthy athlete, with no comorbidities, a normal BMI, vaccinated and boosted, and after an almost asymptomatic bout of COVID-19, a victim to long COVID.

You just never know how your body is going to react. Neuroinflammation occurred in studies with mice with mild respiratory COVID and could be happening to me. I did not want a chronic immune-mediated vasculopathy.

So, I did what any other hyperaware physician-researcher would do. I enrolled in the RECOVER trial – a study my own institution is taking part in and one that I recommend to my own patients.

I also decided that I need to access care and not just ignore my symptoms or try to treat them myself.

That’s when things got difficult. There was a wait of at least a month to see my primary care provider – but I was able to use my privileged position as a physician to get in sooner.

My provider said that she had limited knowledge of long COVID, and she hesitated to order some of the tests and treatments that I recommended because they were not yet considered standard of care. I can understand the hesitation. It is engrained in medical education to follow evidence based on the highest-quality research studies. We are slowly learning more about long COVID, but acknowledging the learning curve offers little to patients who need help now.

This has made me realize that we cannot wait on an evidence-based approach – which can take decades to develop – while people are suffering. And it’s important that everyone on the front line learn about some of the manifestations and disease management of long COVID.

I left this first physician visit feeling more defeated than anything and decided to try to push through. That, I quickly realized, was not the right thing to do.

So again, after a couple of significant crashes and days of severe migraines, I phoned a friend: Ratna Bhavaraju-Sanka, MD, the amazing neurologist who treats patients with long COVID alongside me. She squeezed me in on a non-clinic day. Again, I had the privilege to see a specialist most people wait half a year to see. I was diagnosed with both autonomic dysfunction and intractable migraine.

She ordered some intravenous fluids and IV magnesium that would probably help both. But then another obstacle arose. My institution’s infusion center is focused on patients with cancer, and I was unable to schedule treatments there.

Luckily, I knew about the concierge mobile IV hydration therapy companies that come to your house – mostly offering a hangover treatment service. And I am thankful that I had the health literacy and financial ability to pay for some fluids at home.

On another particularly bad day, I phoned other friends – higher-ups at the hospital – who expedited a slot at the hospital infusion center and approval for the IV magnesium.

Thanks to my access, knowledge, and other privileges, I got fairly quick if imperfect care, enrolled in a research trial, and received medications. I knew to pace myself. The vast majority of others with long COVID lack these advantages.
 

The patient with long COVID

Things I have learned that others can learn, too:

• Acknowledge and recognize that long COVID is a disease that is affecting 1 in 5 Americans who catch COVID. Many look completely “normal on the outside.” Please listen to your patients.
• Autonomic dysfunction is a common manifestation of long COVID. A 10-minute stand test goes a long way in diagnosing this condition, from the American Academy of Physical Medicine and Rehabilitation. It is not just anxiety.
• “That’s only in research” is dismissive and harmful. Think outside the box. Follow guidelines. Consider encouraging patients to sign up for trials.
• Screen for PEM/PESE and teach your patients to pace themselves, because pushing through it or doing graded exercises will be harmful.
• We need to train more physicians to treat postacute sequelae of SARS-CoV-2 infection () and other postinfectious conditions, such as ME/CFS.

If long COVID is hard for physicians to understand and deal with, imagine how difficult it is for patients with no expertise in this area.

It is exponentially harder for those with fewer resources, time, and health literacy. My lived experience with long COVID has shown me that being a patient is never easy. You put your body and fate into the hands of trusted professionals and expect validation and assistance, not gaslighting or gatekeeping.

Along with millions of others, I am tired of waiting.

Dr. Gutierrez is Professor and Distinguished Chair, department of rehabilitation medicine, University of Texas Health Science Center at San Antonio. She reported receiving honoraria for lecturing on long COVID and receiving a research grant from Co-PI for the NIH RECOVER trial.

A version of this article first appeared on Medscape.com.

Psychiatric patients with impaired communication abilities were significantly more likely to be admitted involuntarily to inpatient care and to experience coercive measures after admission, based on data from more than 1,500 individuals.

Despite improvements in reducing coercive measures in psychiatric inpatient care, both involuntary admission and coercive measures remain in use in many countries worldwide, wrote Celline Cole, MSc, a doctoral candidate at Charité Universitätsmedizin, Berlin, and colleagues. Such measures are considered “severe violations of a person’s rights to self-determination and personal freedom,” they wrote.

Previous studies have identified characteristics that increase the risk of involuntary inpatient admission, but the association between patients’ communication ability and coercive measures has not been explored, they noted.

In a study published in the Journal of Psychiatric Research, the investigators reviewed data from 1,556 adults who were admitted to psychiatric inpatient care at a single center in Germany in 2019. Patients’ communication ability was defined and recorded as one of the following: perfect; limited because of language or other reasons; or impossible because of language or other reasons (no communication).

Overall, 23% of patients were admitted involuntarily; the most common reasons for referral to inpatient care in the study population were physical aggression against individuals (8%) or objects (4%), and verbal aggression (7%). A total of 1,085 patients (70%) were able or willing to communicate.

Patients with limited or no communication ability because of language issues were three to four times more likely to be admitted involuntarily (odds ratios, 3.08 and 4.02, respectively), while those with limited or no communication ability because of nonlanguage issues were even more likely to be admitted involuntarily (ORs, 3.10 and 13.71, respectively), compared with patients without communication problems.

Patients with limited communication ability because of language issues also were significantly more likely than those without communication issues to experience coercive measures (OR, 4.53), as were patients with either limited or no communication ability because of no-language issues (ORs, 1.58 and 3.55, respectively).

Involuntary admission was defined as provisional detention, detention initiated by the patient’s legal guardian followed by a court order, or detention by court order “according to the Mental Health Law of the State of Berlin,” the researchers said. The average length of inpatient stay was 19 days. The age of the patients ranged from 18 to 96 years, with a mean age of 41.5 years, and 63% identified as male. Approximately two-thirds (62%) were unemployed or job-seeking during their treatment period, 38% were living alone, and 17% were homeless.

Although most of the study population (84%) was of German nationality, nearly half (48%) had a first- or second-generation migration background, the researchers noted.

“When thinking about effectively targeting this issue it is crucial to consider the different reasons why patients are limited in their ability to communicate,” the researchers wrote in their discussion. “Considering the rising numbers of refugees and persons with a migration background in Germany and many other countries worldwide, it is likely that more and more individuals with a language barrier will present at psychiatric emergency rooms,” they emphasized.

The findings were limited by several factors including the retrospective design, the relatively small number of patients with limitations or complete inability to communicate, and the use of data from a single hospital, and the incomplete data on nonlanguage reasons for limited or no communication ability, the researchers noted. Future studies should include more complete measures for recording these reasons, and data on forced medication, they added.

However, the results were strengthened by the range of sociodemographic, clinical, and admission-related variables in a large and representative sample, and highlight the need for appropriate interventions for patients with communication challenges, they said.

“Adequate financial and human resources need to be allocated to psychiatric hospitals that allow for high quality, available, and accessible interpretation services as well as mobilization of patients’ support networks during and after admission,” they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

Psychiatric patients with impaired communication abilities were significantly more likely to be admitted involuntarily to inpatient care and to experience coercive measures after admission, based on data from more than 1,500 individuals.

Despite improvements in reducing coercive measures in psychiatric inpatient care, both involuntary admission and coercive measures remain in use in many countries worldwide, wrote Celline Cole, MSc, a doctoral candidate at Charité Universitätsmedizin, Berlin, and colleagues. Such measures are considered “severe violations of a person’s rights to self-determination and personal freedom,” they wrote.

Previous studies have identified characteristics that increase the risk of involuntary inpatient admission, but the association between patients’ communication ability and coercive measures has not been explored, they noted.

In a study published in the Journal of Psychiatric Research, the investigators reviewed data from 1,556 adults who were admitted to psychiatric inpatient care at a single center in Germany in 2019. Patients’ communication ability was defined and recorded as one of the following: perfect; limited because of language or other reasons; or impossible because of language or other reasons (no communication).

Overall, 23% of patients were admitted involuntarily; the most common reasons for referral to inpatient care in the study population were physical aggression against individuals (8%) or objects (4%), and verbal aggression (7%). A total of 1,085 patients (70%) were able or willing to communicate.

Patients with limited or no communication ability because of language issues were three to four times more likely to be admitted involuntarily (odds ratios, 3.08 and 4.02, respectively), while those with limited or no communication ability because of nonlanguage issues were even more likely to be admitted involuntarily (ORs, 3.10 and 13.71, respectively), compared with patients without communication problems.

Patients with limited communication ability because of language issues also were significantly more likely than those without communication issues to experience coercive measures (OR, 4.53), as were patients with either limited or no communication ability because of no-language issues (ORs, 1.58 and 3.55, respectively).

Involuntary admission was defined as provisional detention, detention initiated by the patient’s legal guardian followed by a court order, or detention by court order “according to the Mental Health Law of the State of Berlin,” the researchers said. The average length of inpatient stay was 19 days. The age of the patients ranged from 18 to 96 years, with a mean age of 41.5 years, and 63% identified as male. Approximately two-thirds (62%) were unemployed or job-seeking during their treatment period, 38% were living alone, and 17% were homeless.

Although most of the study population (84%) was of German nationality, nearly half (48%) had a first- or second-generation migration background, the researchers noted.

“When thinking about effectively targeting this issue it is crucial to consider the different reasons why patients are limited in their ability to communicate,” the researchers wrote in their discussion. “Considering the rising numbers of refugees and persons with a migration background in Germany and many other countries worldwide, it is likely that more and more individuals with a language barrier will present at psychiatric emergency rooms,” they emphasized.

The findings were limited by several factors including the retrospective design, the relatively small number of patients with limitations or complete inability to communicate, and the use of data from a single hospital, and the incomplete data on nonlanguage reasons for limited or no communication ability, the researchers noted. Future studies should include more complete measures for recording these reasons, and data on forced medication, they added.

However, the results were strengthened by the range of sociodemographic, clinical, and admission-related variables in a large and representative sample, and highlight the need for appropriate interventions for patients with communication challenges, they said.

“Adequate financial and human resources need to be allocated to psychiatric hospitals that allow for high quality, available, and accessible interpretation services as well as mobilization of patients’ support networks during and after admission,” they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

Psychiatric patients with impaired communication abilities were significantly more likely to be admitted involuntarily to inpatient care and to experience coercive measures after admission, based on data from more than 1,500 individuals.

Despite improvements in reducing coercive measures in psychiatric inpatient care, both involuntary admission and coercive measures remain in use in many countries worldwide, wrote Celline Cole, MSc, a doctoral candidate at Charité Universitätsmedizin, Berlin, and colleagues. Such measures are considered “severe violations of a person’s rights to self-determination and personal freedom,” they wrote.

Previous studies have identified characteristics that increase the risk of involuntary inpatient admission, but the association between patients’ communication ability and coercive measures has not been explored, they noted.

In a study published in the Journal of Psychiatric Research, the investigators reviewed data from 1,556 adults who were admitted to psychiatric inpatient care at a single center in Germany in 2019. Patients’ communication ability was defined and recorded as one of the following: perfect; limited because of language or other reasons; or impossible because of language or other reasons (no communication).

Overall, 23% of patients were admitted involuntarily; the most common reasons for referral to inpatient care in the study population were physical aggression against individuals (8%) or objects (4%), and verbal aggression (7%). A total of 1,085 patients (70%) were able or willing to communicate.

Patients with limited or no communication ability because of language issues were three to four times more likely to be admitted involuntarily (odds ratios, 3.08 and 4.02, respectively), while those with limited or no communication ability because of nonlanguage issues were even more likely to be admitted involuntarily (ORs, 3.10 and 13.71, respectively), compared with patients without communication problems.

Patients with limited communication ability because of language issues also were significantly more likely than those without communication issues to experience coercive measures (OR, 4.53), as were patients with either limited or no communication ability because of no-language issues (ORs, 1.58 and 3.55, respectively).

Involuntary admission was defined as provisional detention, detention initiated by the patient’s legal guardian followed by a court order, or detention by court order “according to the Mental Health Law of the State of Berlin,” the researchers said. The average length of inpatient stay was 19 days. The age of the patients ranged from 18 to 96 years, with a mean age of 41.5 years, and 63% identified as male. Approximately two-thirds (62%) were unemployed or job-seeking during their treatment period, 38% were living alone, and 17% were homeless.

Although most of the study population (84%) was of German nationality, nearly half (48%) had a first- or second-generation migration background, the researchers noted.

“When thinking about effectively targeting this issue it is crucial to consider the different reasons why patients are limited in their ability to communicate,” the researchers wrote in their discussion. “Considering the rising numbers of refugees and persons with a migration background in Germany and many other countries worldwide, it is likely that more and more individuals with a language barrier will present at psychiatric emergency rooms,” they emphasized.

The findings were limited by several factors including the retrospective design, the relatively small number of patients with limitations or complete inability to communicate, and the use of data from a single hospital, and the incomplete data on nonlanguage reasons for limited or no communication ability, the researchers noted. Future studies should include more complete measures for recording these reasons, and data on forced medication, they added.

However, the results were strengthened by the range of sociodemographic, clinical, and admission-related variables in a large and representative sample, and highlight the need for appropriate interventions for patients with communication challenges, they said.

“Adequate financial and human resources need to be allocated to psychiatric hospitals that allow for high quality, available, and accessible interpretation services as well as mobilization of patients’ support networks during and after admission,” they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

The McDonald criteria for diagnosing multiple sclerosis (MS) has been around since 2001, with revisions in 2005, 2010, and 2017. They focus on lesions disseminated in space (DIS) and disseminated in time (DIT). As with any diagnostic, new science and methods inform changes. Although optic nerve lesions (ONL) have been considered in past revisions, they have yet to be adopted as a key diagnostic measure of MS.

At the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), several speakers made the case for the addition of ONL to the next McDonald revision. Arguments ranged from the inherent injustice that patients with a diagnosis of optic lesions should have to meet three symptoms of MS to get a diagnosis, while other patients require only two, to the possibility that early presentation with ocular symptoms could be an indicator of a more severe prognosis.

Still, many conditions can mimic the symptoms of ONL, so it is critical to be sure of the diagnosis before considering it a symptom of MS. For example, central serious maculopathy in young to middle-aged patients is often painless and could lead to an inadvertent MS diagnosis if it were added to the criteria. However, treatment with steroids can make it worse, according to Laura Balcer, MD, who spoke at the session. Dr. Balcer is a neuro-ophthalmologist at NYU Langone Health.
 

Adding ONL to McDonald

In the first talk of the session, Frederik Barkhof, MD, PhD, discussed some of the history of the McDonald criteria and laid a groundwork for why it should be updated. He began by pointing out that the latest criteria require either symptomatic or asymptomatic MRI lesions to determine DIS or DIT.

Dr. Barkhof has led the Magnetic Imaging in Multiple Sclerosis (MAGNIMS) group, which had some doubts about the 2017 revision to the McDonald criteria. “We discussed this and said, ‘Well, that is interesting. So you can have a brainstem lesion, which can be the symptomatic lesion and then you need one further region, so you have two regions, and then you have MS. But now if you have an optic nerve presentation, and you can find the optic nerve, it doesn’t count, and then you need two more regions. So there’s a bit of an imbalance. Why would you need three regions if you have an optic nerve, and only two if you have a spinal cord or a brainstem presentation?” recalled Dr. Barkhof, professor of radiology and neuroscience at Vrije Universiteit Amsterdam.

Identifying optic nerve lesions requires a good MRI that should use fat-saturation techniques.

Dr. Barkhof pointed out that the ONLs are a common presentation among MS patients. “We’re now preparing for the next revisions of the McDonnell criteria, and I’m confident and hopeful that we’ll make it this time,” said Dr. Barkhof.
 

Confirm the MS diagnosis

In the second talk, Angela Vidal-Jordana, MD, PhD, discussed ways to implement ONLs in the clinic. She emphasized the importance of ruling out other causes. “Even when a patient comes to us with a diagnosis of optic neuritis, we should question that. Different studies have shown that the optic neuritis overdiagnosis rate at referral might be as high as 60% of the cases,” said Dr. Vidal-Jordana, a neurologist at Centre d’Esclerosi Multiple de Catalunya in Barcelona. Studies show that about half of those are due to misinterpretation of the clinical history and examination, she said.

“So when presenting new visual symptoms, we should ask whether this is suggestive of an inflammatory etiology or not, and whether they are typical for MS or not. If both answers to these questions are yes, then we should apply the diagnostic criteria,” said Dr. Vidal-Jordana.

She presented results from a longitudinal, prospective study conducted within the MAGNIMS network supporting the inclusion of ONL into DIS criteria for MS. It included use of optic nerve MRI, OCT, and VEP [visual evoked potential]. “All of the modified DIS criteria, that is including one of the tests at each time, or a combination of them, led to a higher sensitivity of the diagnostic criteria (when optic nerve involvement was included), albeit with a small decrease in specificity which mainly was due to the fact that we only had 3 years of follow-up. The same held true when analyzing the secondary outcome of new T2 lesions or second relapse during the follow up,” said Dr. Vidal-Jordana.

“As a summary, I would say for sure we will need first of all an MRI, and we need to know if we can evaluate the optic nerve by MRI or not. If not, and we still do not have a diagnosis of a MS, maybe we can order VEP or OCT and then the test selection should be based on the time elapsed since first CIS [clinically isolated syndrome]. If it’s less than 3 months, I would go for a VEP. If it’s more than 3 months, then I probably want to go for OCT,” said Dr. Vidal-Jordana.
 

An aid to earlier diagnosis

In the last talk, Dr. Balcer discussed non-MRI methods for assessing ONLs. She noted that in about 25% of MS patients, ONLs are the first clinical demyelinating event. “Adding the optic nerve to the MS diagnostic criteria will allow us to diagnose our patients even earlier, (it) may help their vision, and could also help us to reduce the overall burden of MS disability over a lifetime. Importantly, entry into MS diagnosis can be delayed among patients for whom optic neuritis or even asymptomatic optic nerve lesions are noted at presentation, and there has been an enormous amount of data that have emerged over the past 5 years demonstrating the importance of the optic nerve in the MS diagnosis with implications for early therapy,” said Dr. Balcer.

She discussed optical coherence tomography (OCT), which is a key technique for diagnosing optic neuropathy. It measures the thickness of the retinal nerve fiber and ganglion cell layers, which have been associated with vision impairment and can reveal asymptomatic involvement of optic nerves in MS.
 

Beware of misdiagnosis

In the Q&A period following the talks, much of the discussion turned to reliability of ONL diagnoses.

“Misdiagnosis is a huge problem. That’s my experience: People who are referred to me with optic neuritis often don’t have optic neuritis,” said comoderator Wallace Brownlee, MBChB, PhD, a consultant neurologist at Cleveland Clinic London. Misha Pless, MD, spoke up from the audience to second that. “I’m delighted that the optic nerve will finally get a place at the table. I’ve been practicing neuro-ophthalmology and I have also [been] an MS doctor for about 25 years. What I see here in this fantastic discussion is that a lot of neurologists are going to be – I hate to use the word ‘misled’ – into relying on technology like OCT, VEP, and MRI to make the diagnosis. I will submit to this panel that that will lead to a number of MS misdiagnoses because I have been doing this for 25 years and the number of patients that I’ve received with rule-out optic neuritis that had macular disease, optical changes, or corneal abrasions are too numerous to count. If you’re going to add optic neuritis in the list of criteria [for MS], you definitely have to have a little asterisk in my opinion and say, ‘with prior blessing from an ophthalmologist to rule out ocular disease,’ because I don’t know any neurologist that knows how to look in the back of the eye, and I don’t know any neurologist that has an OCT in their office,” said Dr. Pless, professor of ophthalmology and a neurologist at Mayo Clinic in Jacksonville, Fla.

The panelists generally agreed with his point, although the hot mic picked up when one panelist whispered to another, ‘I have one,’ referring to an office OCT. “Using OCT in that regard, but also collaborating with your neuro-ophthalmologist and ophthalmologist is critical,” said Dr. Balcer.

Dr. Barkhof has financial relationships with Biogen, Merck, Roche, EISAI, Prothena, IXICO, Jansen, Combinostics, Novartis, GE, Queen Square, and Analytics. Dr. Vidal-Jordana has financial relationships with Roche, Novartis, Merck, and Sanofi. Dr. Balcer has no relevant financial disclosures. Dr. Brownlee has financial relationships with Biogen, Celgene, Merck, Mylan, Novartis, Roche, and Sanofi.

The McDonald criteria for diagnosing multiple sclerosis (MS) has been around since 2001, with revisions in 2005, 2010, and 2017. They focus on lesions disseminated in space (DIS) and disseminated in time (DIT). As with any diagnostic, new science and methods inform changes. Although optic nerve lesions (ONL) have been considered in past revisions, they have yet to be adopted as a key diagnostic measure of MS.

At the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), several speakers made the case for the addition of ONL to the next McDonald revision. Arguments ranged from the inherent injustice that patients with a diagnosis of optic lesions should have to meet three symptoms of MS to get a diagnosis, while other patients require only two, to the possibility that early presentation with ocular symptoms could be an indicator of a more severe prognosis.

Still, many conditions can mimic the symptoms of ONL, so it is critical to be sure of the diagnosis before considering it a symptom of MS. For example, central serious maculopathy in young to middle-aged patients is often painless and could lead to an inadvertent MS diagnosis if it were added to the criteria. However, treatment with steroids can make it worse, according to Laura Balcer, MD, who spoke at the session. Dr. Balcer is a neuro-ophthalmologist at NYU Langone Health.
 

Adding ONL to McDonald

In the first talk of the session, Frederik Barkhof, MD, PhD, discussed some of the history of the McDonald criteria and laid a groundwork for why it should be updated. He began by pointing out that the latest criteria require either symptomatic or asymptomatic MRI lesions to determine DIS or DIT.

Dr. Barkhof has led the Magnetic Imaging in Multiple Sclerosis (MAGNIMS) group, which had some doubts about the 2017 revision to the McDonald criteria. “We discussed this and said, ‘Well, that is interesting. So you can have a brainstem lesion, which can be the symptomatic lesion and then you need one further region, so you have two regions, and then you have MS. But now if you have an optic nerve presentation, and you can find the optic nerve, it doesn’t count, and then you need two more regions. So there’s a bit of an imbalance. Why would you need three regions if you have an optic nerve, and only two if you have a spinal cord or a brainstem presentation?” recalled Dr. Barkhof, professor of radiology and neuroscience at Vrije Universiteit Amsterdam.

Identifying optic nerve lesions requires a good MRI that should use fat-saturation techniques.

Dr. Barkhof pointed out that the ONLs are a common presentation among MS patients. “We’re now preparing for the next revisions of the McDonnell criteria, and I’m confident and hopeful that we’ll make it this time,” said Dr. Barkhof.
 

Confirm the MS diagnosis

In the second talk, Angela Vidal-Jordana, MD, PhD, discussed ways to implement ONLs in the clinic. She emphasized the importance of ruling out other causes. “Even when a patient comes to us with a diagnosis of optic neuritis, we should question that. Different studies have shown that the optic neuritis overdiagnosis rate at referral might be as high as 60% of the cases,” said Dr. Vidal-Jordana, a neurologist at Centre d’Esclerosi Multiple de Catalunya in Barcelona. Studies show that about half of those are due to misinterpretation of the clinical history and examination, she said.

“So when presenting new visual symptoms, we should ask whether this is suggestive of an inflammatory etiology or not, and whether they are typical for MS or not. If both answers to these questions are yes, then we should apply the diagnostic criteria,” said Dr. Vidal-Jordana.

She presented results from a longitudinal, prospective study conducted within the MAGNIMS network supporting the inclusion of ONL into DIS criteria for MS. It included use of optic nerve MRI, OCT, and VEP [visual evoked potential]. “All of the modified DIS criteria, that is including one of the tests at each time, or a combination of them, led to a higher sensitivity of the diagnostic criteria (when optic nerve involvement was included), albeit with a small decrease in specificity which mainly was due to the fact that we only had 3 years of follow-up. The same held true when analyzing the secondary outcome of new T2 lesions or second relapse during the follow up,” said Dr. Vidal-Jordana.

“As a summary, I would say for sure we will need first of all an MRI, and we need to know if we can evaluate the optic nerve by MRI or not. If not, and we still do not have a diagnosis of a MS, maybe we can order VEP or OCT and then the test selection should be based on the time elapsed since first CIS [clinically isolated syndrome]. If it’s less than 3 months, I would go for a VEP. If it’s more than 3 months, then I probably want to go for OCT,” said Dr. Vidal-Jordana.
 

An aid to earlier diagnosis

In the last talk, Dr. Balcer discussed non-MRI methods for assessing ONLs. She noted that in about 25% of MS patients, ONLs are the first clinical demyelinating event. “Adding the optic nerve to the MS diagnostic criteria will allow us to diagnose our patients even earlier, (it) may help their vision, and could also help us to reduce the overall burden of MS disability over a lifetime. Importantly, entry into MS diagnosis can be delayed among patients for whom optic neuritis or even asymptomatic optic nerve lesions are noted at presentation, and there has been an enormous amount of data that have emerged over the past 5 years demonstrating the importance of the optic nerve in the MS diagnosis with implications for early therapy,” said Dr. Balcer.

She discussed optical coherence tomography (OCT), which is a key technique for diagnosing optic neuropathy. It measures the thickness of the retinal nerve fiber and ganglion cell layers, which have been associated with vision impairment and can reveal asymptomatic involvement of optic nerves in MS.
 

Beware of misdiagnosis

In the Q&A period following the talks, much of the discussion turned to reliability of ONL diagnoses.

“Misdiagnosis is a huge problem. That’s my experience: People who are referred to me with optic neuritis often don’t have optic neuritis,” said comoderator Wallace Brownlee, MBChB, PhD, a consultant neurologist at Cleveland Clinic London. Misha Pless, MD, spoke up from the audience to second that. “I’m delighted that the optic nerve will finally get a place at the table. I’ve been practicing neuro-ophthalmology and I have also [been] an MS doctor for about 25 years. What I see here in this fantastic discussion is that a lot of neurologists are going to be – I hate to use the word ‘misled’ – into relying on technology like OCT, VEP, and MRI to make the diagnosis. I will submit to this panel that that will lead to a number of MS misdiagnoses because I have been doing this for 25 years and the number of patients that I’ve received with rule-out optic neuritis that had macular disease, optical changes, or corneal abrasions are too numerous to count. If you’re going to add optic neuritis in the list of criteria [for MS], you definitely have to have a little asterisk in my opinion and say, ‘with prior blessing from an ophthalmologist to rule out ocular disease,’ because I don’t know any neurologist that knows how to look in the back of the eye, and I don’t know any neurologist that has an OCT in their office,” said Dr. Pless, professor of ophthalmology and a neurologist at Mayo Clinic in Jacksonville, Fla.

The panelists generally agreed with his point, although the hot mic picked up when one panelist whispered to another, ‘I have one,’ referring to an office OCT. “Using OCT in that regard, but also collaborating with your neuro-ophthalmologist and ophthalmologist is critical,” said Dr. Balcer.

Dr. Barkhof has financial relationships with Biogen, Merck, Roche, EISAI, Prothena, IXICO, Jansen, Combinostics, Novartis, GE, Queen Square, and Analytics. Dr. Vidal-Jordana has financial relationships with Roche, Novartis, Merck, and Sanofi. Dr. Balcer has no relevant financial disclosures. Dr. Brownlee has financial relationships with Biogen, Celgene, Merck, Mylan, Novartis, Roche, and Sanofi.

The McDonald criteria for diagnosing multiple sclerosis (MS) has been around since 2001, with revisions in 2005, 2010, and 2017. They focus on lesions disseminated in space (DIS) and disseminated in time (DIT). As with any diagnostic, new science and methods inform changes. Although optic nerve lesions (ONL) have been considered in past revisions, they have yet to be adopted as a key diagnostic measure of MS.

At the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), several speakers made the case for the addition of ONL to the next McDonald revision. Arguments ranged from the inherent injustice that patients with a diagnosis of optic lesions should have to meet three symptoms of MS to get a diagnosis, while other patients require only two, to the possibility that early presentation with ocular symptoms could be an indicator of a more severe prognosis.

Still, many conditions can mimic the symptoms of ONL, so it is critical to be sure of the diagnosis before considering it a symptom of MS. For example, central serious maculopathy in young to middle-aged patients is often painless and could lead to an inadvertent MS diagnosis if it were added to the criteria. However, treatment with steroids can make it worse, according to Laura Balcer, MD, who spoke at the session. Dr. Balcer is a neuro-ophthalmologist at NYU Langone Health.
 

Adding ONL to McDonald

In the first talk of the session, Frederik Barkhof, MD, PhD, discussed some of the history of the McDonald criteria and laid a groundwork for why it should be updated. He began by pointing out that the latest criteria require either symptomatic or asymptomatic MRI lesions to determine DIS or DIT.

Dr. Barkhof has led the Magnetic Imaging in Multiple Sclerosis (MAGNIMS) group, which had some doubts about the 2017 revision to the McDonald criteria. “We discussed this and said, ‘Well, that is interesting. So you can have a brainstem lesion, which can be the symptomatic lesion and then you need one further region, so you have two regions, and then you have MS. But now if you have an optic nerve presentation, and you can find the optic nerve, it doesn’t count, and then you need two more regions. So there’s a bit of an imbalance. Why would you need three regions if you have an optic nerve, and only two if you have a spinal cord or a brainstem presentation?” recalled Dr. Barkhof, professor of radiology and neuroscience at Vrije Universiteit Amsterdam.

Identifying optic nerve lesions requires a good MRI that should use fat-saturation techniques.

Dr. Barkhof pointed out that the ONLs are a common presentation among MS patients. “We’re now preparing for the next revisions of the McDonnell criteria, and I’m confident and hopeful that we’ll make it this time,” said Dr. Barkhof.
 

Confirm the MS diagnosis

In the second talk, Angela Vidal-Jordana, MD, PhD, discussed ways to implement ONLs in the clinic. She emphasized the importance of ruling out other causes. “Even when a patient comes to us with a diagnosis of optic neuritis, we should question that. Different studies have shown that the optic neuritis overdiagnosis rate at referral might be as high as 60% of the cases,” said Dr. Vidal-Jordana, a neurologist at Centre d’Esclerosi Multiple de Catalunya in Barcelona. Studies show that about half of those are due to misinterpretation of the clinical history and examination, she said.

“So when presenting new visual symptoms, we should ask whether this is suggestive of an inflammatory etiology or not, and whether they are typical for MS or not. If both answers to these questions are yes, then we should apply the diagnostic criteria,” said Dr. Vidal-Jordana.

She presented results from a longitudinal, prospective study conducted within the MAGNIMS network supporting the inclusion of ONL into DIS criteria for MS. It included use of optic nerve MRI, OCT, and VEP [visual evoked potential]. “All of the modified DIS criteria, that is including one of the tests at each time, or a combination of them, led to a higher sensitivity of the diagnostic criteria (when optic nerve involvement was included), albeit with a small decrease in specificity which mainly was due to the fact that we only had 3 years of follow-up. The same held true when analyzing the secondary outcome of new T2 lesions or second relapse during the follow up,” said Dr. Vidal-Jordana.

“As a summary, I would say for sure we will need first of all an MRI, and we need to know if we can evaluate the optic nerve by MRI or not. If not, and we still do not have a diagnosis of a MS, maybe we can order VEP or OCT and then the test selection should be based on the time elapsed since first CIS [clinically isolated syndrome]. If it’s less than 3 months, I would go for a VEP. If it’s more than 3 months, then I probably want to go for OCT,” said Dr. Vidal-Jordana.
 

An aid to earlier diagnosis

In the last talk, Dr. Balcer discussed non-MRI methods for assessing ONLs. She noted that in about 25% of MS patients, ONLs are the first clinical demyelinating event. “Adding the optic nerve to the MS diagnostic criteria will allow us to diagnose our patients even earlier, (it) may help their vision, and could also help us to reduce the overall burden of MS disability over a lifetime. Importantly, entry into MS diagnosis can be delayed among patients for whom optic neuritis or even asymptomatic optic nerve lesions are noted at presentation, and there has been an enormous amount of data that have emerged over the past 5 years demonstrating the importance of the optic nerve in the MS diagnosis with implications for early therapy,” said Dr. Balcer.

She discussed optical coherence tomography (OCT), which is a key technique for diagnosing optic neuropathy. It measures the thickness of the retinal nerve fiber and ganglion cell layers, which have been associated with vision impairment and can reveal asymptomatic involvement of optic nerves in MS.
 

Beware of misdiagnosis

In the Q&A period following the talks, much of the discussion turned to reliability of ONL diagnoses.

“Misdiagnosis is a huge problem. That’s my experience: People who are referred to me with optic neuritis often don’t have optic neuritis,” said comoderator Wallace Brownlee, MBChB, PhD, a consultant neurologist at Cleveland Clinic London. Misha Pless, MD, spoke up from the audience to second that. “I’m delighted that the optic nerve will finally get a place at the table. I’ve been practicing neuro-ophthalmology and I have also [been] an MS doctor for about 25 years. What I see here in this fantastic discussion is that a lot of neurologists are going to be – I hate to use the word ‘misled’ – into relying on technology like OCT, VEP, and MRI to make the diagnosis. I will submit to this panel that that will lead to a number of MS misdiagnoses because I have been doing this for 25 years and the number of patients that I’ve received with rule-out optic neuritis that had macular disease, optical changes, or corneal abrasions are too numerous to count. If you’re going to add optic neuritis in the list of criteria [for MS], you definitely have to have a little asterisk in my opinion and say, ‘with prior blessing from an ophthalmologist to rule out ocular disease,’ because I don’t know any neurologist that knows how to look in the back of the eye, and I don’t know any neurologist that has an OCT in their office,” said Dr. Pless, professor of ophthalmology and a neurologist at Mayo Clinic in Jacksonville, Fla.

The panelists generally agreed with his point, although the hot mic picked up when one panelist whispered to another, ‘I have one,’ referring to an office OCT. “Using OCT in that regard, but also collaborating with your neuro-ophthalmologist and ophthalmologist is critical,” said Dr. Balcer.

Dr. Barkhof has financial relationships with Biogen, Merck, Roche, EISAI, Prothena, IXICO, Jansen, Combinostics, Novartis, GE, Queen Square, and Analytics. Dr. Vidal-Jordana has financial relationships with Roche, Novartis, Merck, and Sanofi. Dr. Balcer has no relevant financial disclosures. Dr. Brownlee has financial relationships with Biogen, Celgene, Merck, Mylan, Novartis, Roche, and Sanofi.

Comprehensive evaluation, multidisciplinary care, individualized treatment, and ongoing follow-up are all key to the management of pediatric thyroid nodules and differentiated thyroid carcinoma (DTC), according to the first European guidelines for this rare disease.

The guidelines were recently published in the European Thyroid Journal.

Lead author Chantal A. Lebbink told this news organization one of the key takeaways for clinicians is that management of pediatric thyroid nodules and DTC is «challenging and cannot be captured in a one-size-fits-all model.”

She also underlined the need for a “multidisciplinary approach in pediatric thyroid cancer expertise centers.”

Above all, Ms. Lebbink, who is a PhD student in the department of pediatric endocrinology, Wilhelmina Children’s Hospital, Utrecht, the Netherlands, said that pediatric DTC “is not adult DTC in a small person; it has different genetics and a different clinical behavior.”

The authors noted that DTC may be a rare disease, but its worldwide incidence is rising. It has several histologic subtypes, although the “vast majority” of cases are papillary thyroid carcinoma.

Crucially, there are “important differences” between adult and pediatric DTC in terms of their clinical, molecular, and pathologic characteristics, with pediatric patients commonly presenting with more advanced disease with greater lymph node involvement, distant metastases, and multifocal disease.

“However, despite the aggressive presentation, the overall survival rates are excellent,” Ms. Lebbink said.

There are also differences in genetic alterations between adult and pediatric patients. RET-PTC and NTRK fusions are more common in pediatric patients, while mutations in BRAF V600E and RAS point mutations are less frequent.
 

First European guidelines on thyroid cancer, thyroid nodules in children

Despite these differences, and the existence of U.S. guidelines, until now there have been no European recommendations on the management of pediatric thyroid nodules and DTC.

The European Thyroid Association therefore convened a panel of experts in pediatric and adult endocrinology, pathology, endocrine surgery, nuclear medicine, clinical genetics, and oncology, and tasked them with looking at diagnostics and staging, treatment, and follow-up.

The 2015 American Thyroid Association pediatric guideline was used as framework for the European guideline, with the expert panel identifying areas of discordance and outstanding clinical questions (Thyroid. 2015 Jul;25[7]:716-59).

To answer these questions, they searched PubMed and identified 3,251 studies, of which 45 studies met the inclusion criteria. From this they developed a comprehensive set of recommendations. These include that a child with suspected or proven cancer be referred to an experienced multidisciplinary team and their likely benefit from higher- versus lower-intensity treatment be established.

In addition, children should undergo a preoperative evaluation, with neck palpation, comprehensive neck ultrasonography, and laboratory work-up as a minimum, with further testing suggested in case of a family history or extensive disease.

Total thyroidectomy is the recommended treatment, although the authors call for further studies to assess the impact of limited surgery, and they suggest that prophylactic central lymph node dissection be reserved for advanced cases.

Crucially, all children “should be operated on by high-volume pediatric thyroid cancer surgeons with experience in pediatric thyroid cancer and who are embedded in a center with expertise in the management of DTC,” they wrote.
 

RAI therapy recommended for all children, in contrast to ATA guidelines

Radioactive iodine (I-131) therapy is recommended for all children following total thyroidectomy, with treatment following an individual patient-based approach.

This differs slightly from the ATA guidelines, which recommend against radioactive iodine (RAI) therapy for children with low-risk differentiated thyroid cancer that is mostly confined to the thyroid (N0 or minimal N1a disease). A study presented at the recent 2022 annual meeting of the ATA found that such children who were spared RAI showed no increases in risk of remission compared with those who did receive it.

The ETA guidelines then go on to recommend that children should be followed up with thyroid-stimulating hormone monitoring and suppression to low-normal levels, as well as serum thyroglobulin measurement and neck ultrasound, although other imaging modalities are not recommended.

In children with persistent or recurrent cervical disease, “surgery or I-131 therapy are indicated depending on the size, tumor load, and degree of progression,” and the authors said that cases of radioactive refractory disease should be “thoroughly investigated.”

Patients should also be counseled on the risk of the late effects of treatment for DTC and undergo monitoring, with follow-up continued for at least 10 years. Any subsequent follow-up should be “the result of shared decision-making between the physician and the patient.”
 

Evidence for molecular testing is scarce

Ms. Lebbink said that developing the guidelines nevertheless revealed a series of gaps in current knowledge, notably that the evidence for molecular testing “and the clinical implications in the preoperative stage are scarce.”

Specifically, the “positive and negative predictive value of molecular testing in fine needle biopsy specimen for the presence of DTC in a thyroid nodule must be further investigated.»

She also said that there has been a shift towards less aggressive treatment, due to a reluctance to performed prophylactic central neck dissection, and to offer I-131 therapy after surgery.

“However, before less aggressive treatment could be recommended,” Ms. Lebbink said, “it first must be investigated if there are differences in outcomes,” such as recurrence rates, disease-free survival rates, and survival rates between patients who do and do not receive the treatments.

No funding was declared. One author has reported relationships with Sanofi, AstraZeneca, Bayer, and GE. No other relevant financial relationships were reported.

A version of this article first appeared on Medscape.com.

Comprehensive evaluation, multidisciplinary care, individualized treatment, and ongoing follow-up are all key to the management of pediatric thyroid nodules and differentiated thyroid carcinoma (DTC), according to the first European guidelines for this rare disease.

The guidelines were recently published in the European Thyroid Journal.

Lead author Chantal A. Lebbink told this news organization one of the key takeaways for clinicians is that management of pediatric thyroid nodules and DTC is «challenging and cannot be captured in a one-size-fits-all model.”

She also underlined the need for a “multidisciplinary approach in pediatric thyroid cancer expertise centers.”

Above all, Ms. Lebbink, who is a PhD student in the department of pediatric endocrinology, Wilhelmina Children’s Hospital, Utrecht, the Netherlands, said that pediatric DTC “is not adult DTC in a small person; it has different genetics and a different clinical behavior.”

The authors noted that DTC may be a rare disease, but its worldwide incidence is rising. It has several histologic subtypes, although the “vast majority” of cases are papillary thyroid carcinoma.

Crucially, there are “important differences” between adult and pediatric DTC in terms of their clinical, molecular, and pathologic characteristics, with pediatric patients commonly presenting with more advanced disease with greater lymph node involvement, distant metastases, and multifocal disease.

“However, despite the aggressive presentation, the overall survival rates are excellent,” Ms. Lebbink said.

There are also differences in genetic alterations between adult and pediatric patients. RET-PTC and NTRK fusions are more common in pediatric patients, while mutations in BRAF V600E and RAS point mutations are less frequent.
 

First European guidelines on thyroid cancer, thyroid nodules in children

Despite these differences, and the existence of U.S. guidelines, until now there have been no European recommendations on the management of pediatric thyroid nodules and DTC.

The European Thyroid Association therefore convened a panel of experts in pediatric and adult endocrinology, pathology, endocrine surgery, nuclear medicine, clinical genetics, and oncology, and tasked them with looking at diagnostics and staging, treatment, and follow-up.

The 2015 American Thyroid Association pediatric guideline was used as framework for the European guideline, with the expert panel identifying areas of discordance and outstanding clinical questions (Thyroid. 2015 Jul;25[7]:716-59).

To answer these questions, they searched PubMed and identified 3,251 studies, of which 45 studies met the inclusion criteria. From this they developed a comprehensive set of recommendations. These include that a child with suspected or proven cancer be referred to an experienced multidisciplinary team and their likely benefit from higher- versus lower-intensity treatment be established.

In addition, children should undergo a preoperative evaluation, with neck palpation, comprehensive neck ultrasonography, and laboratory work-up as a minimum, with further testing suggested in case of a family history or extensive disease.

Total thyroidectomy is the recommended treatment, although the authors call for further studies to assess the impact of limited surgery, and they suggest that prophylactic central lymph node dissection be reserved for advanced cases.

Crucially, all children “should be operated on by high-volume pediatric thyroid cancer surgeons with experience in pediatric thyroid cancer and who are embedded in a center with expertise in the management of DTC,” they wrote.
 

RAI therapy recommended for all children, in contrast to ATA guidelines

Radioactive iodine (I-131) therapy is recommended for all children following total thyroidectomy, with treatment following an individual patient-based approach.

This differs slightly from the ATA guidelines, which recommend against radioactive iodine (RAI) therapy for children with low-risk differentiated thyroid cancer that is mostly confined to the thyroid (N0 or minimal N1a disease). A study presented at the recent 2022 annual meeting of the ATA found that such children who were spared RAI showed no increases in risk of remission compared with those who did receive it.

The ETA guidelines then go on to recommend that children should be followed up with thyroid-stimulating hormone monitoring and suppression to low-normal levels, as well as serum thyroglobulin measurement and neck ultrasound, although other imaging modalities are not recommended.

In children with persistent or recurrent cervical disease, “surgery or I-131 therapy are indicated depending on the size, tumor load, and degree of progression,” and the authors said that cases of radioactive refractory disease should be “thoroughly investigated.”

Patients should also be counseled on the risk of the late effects of treatment for DTC and undergo monitoring, with follow-up continued for at least 10 years. Any subsequent follow-up should be “the result of shared decision-making between the physician and the patient.”
 

Evidence for molecular testing is scarce

Ms. Lebbink said that developing the guidelines nevertheless revealed a series of gaps in current knowledge, notably that the evidence for molecular testing “and the clinical implications in the preoperative stage are scarce.”

Specifically, the “positive and negative predictive value of molecular testing in fine needle biopsy specimen for the presence of DTC in a thyroid nodule must be further investigated.»

She also said that there has been a shift towards less aggressive treatment, due to a reluctance to performed prophylactic central neck dissection, and to offer I-131 therapy after surgery.

“However, before less aggressive treatment could be recommended,” Ms. Lebbink said, “it first must be investigated if there are differences in outcomes,” such as recurrence rates, disease-free survival rates, and survival rates between patients who do and do not receive the treatments.

No funding was declared. One author has reported relationships with Sanofi, AstraZeneca, Bayer, and GE. No other relevant financial relationships were reported.

A version of this article first appeared on Medscape.com.

Comprehensive evaluation, multidisciplinary care, individualized treatment, and ongoing follow-up are all key to the management of pediatric thyroid nodules and differentiated thyroid carcinoma (DTC), according to the first European guidelines for this rare disease.

The guidelines were recently published in the European Thyroid Journal.

Lead author Chantal A. Lebbink told this news organization one of the key takeaways for clinicians is that management of pediatric thyroid nodules and DTC is «challenging and cannot be captured in a one-size-fits-all model.”

She also underlined the need for a “multidisciplinary approach in pediatric thyroid cancer expertise centers.”

Above all, Ms. Lebbink, who is a PhD student in the department of pediatric endocrinology, Wilhelmina Children’s Hospital, Utrecht, the Netherlands, said that pediatric DTC “is not adult DTC in a small person; it has different genetics and a different clinical behavior.”

The authors noted that DTC may be a rare disease, but its worldwide incidence is rising. It has several histologic subtypes, although the “vast majority” of cases are papillary thyroid carcinoma.

Crucially, there are “important differences” between adult and pediatric DTC in terms of their clinical, molecular, and pathologic characteristics, with pediatric patients commonly presenting with more advanced disease with greater lymph node involvement, distant metastases, and multifocal disease.

“However, despite the aggressive presentation, the overall survival rates are excellent,” Ms. Lebbink said.

There are also differences in genetic alterations between adult and pediatric patients. RET-PTC and NTRK fusions are more common in pediatric patients, while mutations in BRAF V600E and RAS point mutations are less frequent.
 

First European guidelines on thyroid cancer, thyroid nodules in children

Despite these differences, and the existence of U.S. guidelines, until now there have been no European recommendations on the management of pediatric thyroid nodules and DTC.

The European Thyroid Association therefore convened a panel of experts in pediatric and adult endocrinology, pathology, endocrine surgery, nuclear medicine, clinical genetics, and oncology, and tasked them with looking at diagnostics and staging, treatment, and follow-up.

The 2015 American Thyroid Association pediatric guideline was used as framework for the European guideline, with the expert panel identifying areas of discordance and outstanding clinical questions (Thyroid. 2015 Jul;25[7]:716-59).

To answer these questions, they searched PubMed and identified 3,251 studies, of which 45 studies met the inclusion criteria. From this they developed a comprehensive set of recommendations. These include that a child with suspected or proven cancer be referred to an experienced multidisciplinary team and their likely benefit from higher- versus lower-intensity treatment be established.

In addition, children should undergo a preoperative evaluation, with neck palpation, comprehensive neck ultrasonography, and laboratory work-up as a minimum, with further testing suggested in case of a family history or extensive disease.

Total thyroidectomy is the recommended treatment, although the authors call for further studies to assess the impact of limited surgery, and they suggest that prophylactic central lymph node dissection be reserved for advanced cases.

Crucially, all children “should be operated on by high-volume pediatric thyroid cancer surgeons with experience in pediatric thyroid cancer and who are embedded in a center with expertise in the management of DTC,” they wrote.
 

RAI therapy recommended for all children, in contrast to ATA guidelines

Radioactive iodine (I-131) therapy is recommended for all children following total thyroidectomy, with treatment following an individual patient-based approach.

This differs slightly from the ATA guidelines, which recommend against radioactive iodine (RAI) therapy for children with low-risk differentiated thyroid cancer that is mostly confined to the thyroid (N0 or minimal N1a disease). A study presented at the recent 2022 annual meeting of the ATA found that such children who were spared RAI showed no increases in risk of remission compared with those who did receive it.

The ETA guidelines then go on to recommend that children should be followed up with thyroid-stimulating hormone monitoring and suppression to low-normal levels, as well as serum thyroglobulin measurement and neck ultrasound, although other imaging modalities are not recommended.

In children with persistent or recurrent cervical disease, “surgery or I-131 therapy are indicated depending on the size, tumor load, and degree of progression,” and the authors said that cases of radioactive refractory disease should be “thoroughly investigated.”

Patients should also be counseled on the risk of the late effects of treatment for DTC and undergo monitoring, with follow-up continued for at least 10 years. Any subsequent follow-up should be “the result of shared decision-making between the physician and the patient.”
 

Evidence for molecular testing is scarce

Ms. Lebbink said that developing the guidelines nevertheless revealed a series of gaps in current knowledge, notably that the evidence for molecular testing “and the clinical implications in the preoperative stage are scarce.”

Specifically, the “positive and negative predictive value of molecular testing in fine needle biopsy specimen for the presence of DTC in a thyroid nodule must be further investigated.»

She also said that there has been a shift towards less aggressive treatment, due to a reluctance to performed prophylactic central neck dissection, and to offer I-131 therapy after surgery.

“However, before less aggressive treatment could be recommended,” Ms. Lebbink said, “it first must be investigated if there are differences in outcomes,” such as recurrence rates, disease-free survival rates, and survival rates between patients who do and do not receive the treatments.

No funding was declared. One author has reported relationships with Sanofi, AstraZeneca, Bayer, and GE. No other relevant financial relationships were reported.

A version of this article first appeared on Medscape.com.

In a subgroup of patients with hepatorenal syndrome type 1 (HRS) who received a liver transplant, terlipressin treatment appears to reduce the need for renal replacement therapy (RRT) through 12 months of follow-up, according to a study presented at the annual meeting of the American College of Gastroenterology.

Among transplant recipients, overall 12-month survival was 11% higher for those treated with terlipressin compared with placebo, said K. Rajender Reddy, MD, director of hepatology and medical director of liver transplantation at the University of Pennsylvania, Philadelphia.

“Hepatorenal syndrome type 1 is a potentially reversible form of acute kidney injury that occurs in the setting of end-stage liver disease,” he said.

Liver transplantation, which eliminates end-stage liver disease, is the only definitive treatment for HRS. However, renal replacement therapy is common and associated with poor clinical outcomes and low patient survival rates in both the pretransplant and posttransplant settings, he noted.

Terlipressin, an injectable synthetic vasopressin analogue, restores renal blood flow and reverses HRS in 20%-40% of patients, Dr. Reddy said. In September, the U.S. Food and Drug Administration approved terlipressin (Terlivaz) for patients with HRS type 1. The label has a boxed warning for serious or fatal respiratory failure.

The safety and efficacy were assessed in the phase 3 CONFIRM trial, which Dr. Reddy and colleagues previously published. The randomized, placebo-controlled study demonstrated that terlipressin reversed HRS and reduced the need for RRT through day 30. The reversal of HRS with terlipressin did not improve 90-day survival as compared with placebo, which researchers attributed to a higher death rate within 90 days after the first dose despite improved kidney function.

A closer look at the liver transplant patients

In the subgroup analysis of the CONFIRM study, Dr. Reddy and colleagues analyzed the clinical outcomes through 12 months of follow-up in patients with HRS who received a liver transplant. They looked at the incidence of verified HRS reversal, HRS reversal, need for RRT, and overall survival.

Verified HRS reversal was defined as two consecutive serum creatinine measurements of 1.5 mg/dL or less at least 2 hours apart up to day 14 and survival without RRT for at least 10 days. HRS reversal was defined as a serum creatinine level of 1.5 mg/dL or less while on treatment. In addition, the need for RRT and overall survival were assessed at days 30, 60, 90, 180, and 365.

RRT was defined as any procedure that replaced nonendocrine kidney function, including continuous hemofiltration and hemodialysis, intermittent hemodialysis, peritoneal dialysis, ultrafiltration, or other dialysis and filtration techniques.

In the CONFIRM study, 199 patients with HRS were treated with terlipressin plus albumin, and 101 patients were treated with placebo plus albumin for up to 14 days. In the terlipressin group, 46 patients received liver transplants within the first 2 months of the study, as did 29 in the placebo group. Two patients in the terlipressin group and one in the placebo group received a simultaneous liver-kidney transplant.
 

Meaningful clinical outcomes

In the 12-month follow-up subgroup analysis, verified HRS reversal was statistically comparable between the groups, with a 30% decrease in the terlipressin group and 17% decrease in the placebo group, Dr. Reddy reported.

HRS reversal was higher in the terlipressin group, at 37%, as compared with 14% in the placebo group.

The pretransplant need for RRT was lower in the terlipressin group, at 30%, as compared with 62% in the placebo group. The posttransplant need for RRT remained numerically lower in the terlipressin group at all time points and was significantly lower at day 180 and day 365.

Overall survival for transplant recipients in the terlipressin group was 94%, as compared with 83% in the placebo group. Posttreatment adverse events and severe adverse events were similar between the groups.

“Collectively, these data indicate that terlipressin treatment in patients with HRS led to better long-term clinical outcomes in those who received a liver transplant,” Dr. Reddy said.

The study was funded by Mallinckrodt Pharmaceuticals, which manufactures terlipressin. One author is an employee of Mallinckrodt, and the other authors have served in an advisory role or received grant support from Mallinckrodt. The authors also disclosed consultant roles and research support from several other pharmaceutical companies.

In a subgroup of patients with hepatorenal syndrome type 1 (HRS) who received a liver transplant, terlipressin treatment appears to reduce the need for renal replacement therapy (RRT) through 12 months of follow-up, according to a study presented at the annual meeting of the American College of Gastroenterology.

Among transplant recipients, overall 12-month survival was 11% higher for those treated with terlipressin compared with placebo, said K. Rajender Reddy, MD, director of hepatology and medical director of liver transplantation at the University of Pennsylvania, Philadelphia.

“Hepatorenal syndrome type 1 is a potentially reversible form of acute kidney injury that occurs in the setting of end-stage liver disease,” he said.

Liver transplantation, which eliminates end-stage liver disease, is the only definitive treatment for HRS. However, renal replacement therapy is common and associated with poor clinical outcomes and low patient survival rates in both the pretransplant and posttransplant settings, he noted.

Terlipressin, an injectable synthetic vasopressin analogue, restores renal blood flow and reverses HRS in 20%-40% of patients, Dr. Reddy said. In September, the U.S. Food and Drug Administration approved terlipressin (Terlivaz) for patients with HRS type 1. The label has a boxed warning for serious or fatal respiratory failure.

The safety and efficacy were assessed in the phase 3 CONFIRM trial, which Dr. Reddy and colleagues previously published. The randomized, placebo-controlled study demonstrated that terlipressin reversed HRS and reduced the need for RRT through day 30. The reversal of HRS with terlipressin did not improve 90-day survival as compared with placebo, which researchers attributed to a higher death rate within 90 days after the first dose despite improved kidney function.

A closer look at the liver transplant patients

In the subgroup analysis of the CONFIRM study, Dr. Reddy and colleagues analyzed the clinical outcomes through 12 months of follow-up in patients with HRS who received a liver transplant. They looked at the incidence of verified HRS reversal, HRS reversal, need for RRT, and overall survival.

Verified HRS reversal was defined as two consecutive serum creatinine measurements of 1.5 mg/dL or less at least 2 hours apart up to day 14 and survival without RRT for at least 10 days. HRS reversal was defined as a serum creatinine level of 1.5 mg/dL or less while on treatment. In addition, the need for RRT and overall survival were assessed at days 30, 60, 90, 180, and 365.

RRT was defined as any procedure that replaced nonendocrine kidney function, including continuous hemofiltration and hemodialysis, intermittent hemodialysis, peritoneal dialysis, ultrafiltration, or other dialysis and filtration techniques.

In the CONFIRM study, 199 patients with HRS were treated with terlipressin plus albumin, and 101 patients were treated with placebo plus albumin for up to 14 days. In the terlipressin group, 46 patients received liver transplants within the first 2 months of the study, as did 29 in the placebo group. Two patients in the terlipressin group and one in the placebo group received a simultaneous liver-kidney transplant.
 

Meaningful clinical outcomes

In the 12-month follow-up subgroup analysis, verified HRS reversal was statistically comparable between the groups, with a 30% decrease in the terlipressin group and 17% decrease in the placebo group, Dr. Reddy reported.

HRS reversal was higher in the terlipressin group, at 37%, as compared with 14% in the placebo group.

The pretransplant need for RRT was lower in the terlipressin group, at 30%, as compared with 62% in the placebo group. The posttransplant need for RRT remained numerically lower in the terlipressin group at all time points and was significantly lower at day 180 and day 365.

Overall survival for transplant recipients in the terlipressin group was 94%, as compared with 83% in the placebo group. Posttreatment adverse events and severe adverse events were similar between the groups.

“Collectively, these data indicate that terlipressin treatment in patients with HRS led to better long-term clinical outcomes in those who received a liver transplant,” Dr. Reddy said.

The study was funded by Mallinckrodt Pharmaceuticals, which manufactures terlipressin. One author is an employee of Mallinckrodt, and the other authors have served in an advisory role or received grant support from Mallinckrodt. The authors also disclosed consultant roles and research support from several other pharmaceutical companies.

In a subgroup of patients with hepatorenal syndrome type 1 (HRS) who received a liver transplant, terlipressin treatment appears to reduce the need for renal replacement therapy (RRT) through 12 months of follow-up, according to a study presented at the annual meeting of the American College of Gastroenterology.

Among transplant recipients, overall 12-month survival was 11% higher for those treated with terlipressin compared with placebo, said K. Rajender Reddy, MD, director of hepatology and medical director of liver transplantation at the University of Pennsylvania, Philadelphia.

“Hepatorenal syndrome type 1 is a potentially reversible form of acute kidney injury that occurs in the setting of end-stage liver disease,” he said.

Liver transplantation, which eliminates end-stage liver disease, is the only definitive treatment for HRS. However, renal replacement therapy is common and associated with poor clinical outcomes and low patient survival rates in both the pretransplant and posttransplant settings, he noted.

Terlipressin, an injectable synthetic vasopressin analogue, restores renal blood flow and reverses HRS in 20%-40% of patients, Dr. Reddy said. In September, the U.S. Food and Drug Administration approved terlipressin (Terlivaz) for patients with HRS type 1. The label has a boxed warning for serious or fatal respiratory failure.

The safety and efficacy were assessed in the phase 3 CONFIRM trial, which Dr. Reddy and colleagues previously published. The randomized, placebo-controlled study demonstrated that terlipressin reversed HRS and reduced the need for RRT through day 30. The reversal of HRS with terlipressin did not improve 90-day survival as compared with placebo, which researchers attributed to a higher death rate within 90 days after the first dose despite improved kidney function.

A closer look at the liver transplant patients

In the subgroup analysis of the CONFIRM study, Dr. Reddy and colleagues analyzed the clinical outcomes through 12 months of follow-up in patients with HRS who received a liver transplant. They looked at the incidence of verified HRS reversal, HRS reversal, need for RRT, and overall survival.

Verified HRS reversal was defined as two consecutive serum creatinine measurements of 1.5 mg/dL or less at least 2 hours apart up to day 14 and survival without RRT for at least 10 days. HRS reversal was defined as a serum creatinine level of 1.5 mg/dL or less while on treatment. In addition, the need for RRT and overall survival were assessed at days 30, 60, 90, 180, and 365.

RRT was defined as any procedure that replaced nonendocrine kidney function, including continuous hemofiltration and hemodialysis, intermittent hemodialysis, peritoneal dialysis, ultrafiltration, or other dialysis and filtration techniques.

In the CONFIRM study, 199 patients with HRS were treated with terlipressin plus albumin, and 101 patients were treated with placebo plus albumin for up to 14 days. In the terlipressin group, 46 patients received liver transplants within the first 2 months of the study, as did 29 in the placebo group. Two patients in the terlipressin group and one in the placebo group received a simultaneous liver-kidney transplant.
 

Meaningful clinical outcomes

In the 12-month follow-up subgroup analysis, verified HRS reversal was statistically comparable between the groups, with a 30% decrease in the terlipressin group and 17% decrease in the placebo group, Dr. Reddy reported.

HRS reversal was higher in the terlipressin group, at 37%, as compared with 14% in the placebo group.

The pretransplant need for RRT was lower in the terlipressin group, at 30%, as compared with 62% in the placebo group. The posttransplant need for RRT remained numerically lower in the terlipressin group at all time points and was significantly lower at day 180 and day 365.

Overall survival for transplant recipients in the terlipressin group was 94%, as compared with 83% in the placebo group. Posttreatment adverse events and severe adverse events were similar between the groups.

“Collectively, these data indicate that terlipressin treatment in patients with HRS led to better long-term clinical outcomes in those who received a liver transplant,” Dr. Reddy said.

The study was funded by Mallinckrodt Pharmaceuticals, which manufactures terlipressin. One author is an employee of Mallinckrodt, and the other authors have served in an advisory role or received grant support from Mallinckrodt. The authors also disclosed consultant roles and research support from several other pharmaceutical companies.

CHARLOTTE, N.C. – RBX2660 could be a new option for people who experience recurrent, debilitating Clostridioides difficile infections.

Following a standard course of antibiotics, a one-time treatment with RBX2660 was successful for three quarters of participants at 8 weeks, according to a new study. It also prevented additional bouts, with 84% of these initial responders remaining free of C. difficile infection at 6 months.

The ongoing phase 3, open-label PUNCH CD3-OLS study expands on clinical trial experience by treating more “real-world” patients. People who might have been excluded from previous research because of comorbidities, such as irritable bowel syndrome, inflammatory bowel disease, and immunosuppression, were included.

The study also placed no limit on the number of previous rounds of C. difficile infections.

“Even when you expand the patient population to make it more generalizable, we’re still seeing both a high cure rate and a high success rate,” Sahil Khanna, MBBS, a gastroenterologist and hepatologist at the Mayo Clinic in Rochester, Minn., said in an interview.

“We also are not seeing any kind of safety signals that can be attributed to this particular product,” he said.

Dr. Khanna presented the findings during the annual meeting of the American College of Gastroenterology, which were also published simultaneously in the journal Drugs. The research by Dr. Khanna and associates received an ACG Outstanding Research Award in the colon category.
 

Study design and results

RBX2660 (Rebyota) is a microbiota-based live biotherapeutic in development from Ferring Pharmaceuticals. The treatment contains human stool collected from prescreened, qualified donors and is prepared according to good manufacturing standards.

After standard-of-care antibiotics and a 72-hour washout period, participants received a single 150-mL dose rectally by enema. RBX2660 is administered by a health care professional.

The median age of study participants was 63 years, with 45% aged 65 years or older, and 70% were women. Overall, 37% of participants had Crohn’s disease and 4% had ulcerative colitis.

At the time of screening, about half of participants had a history of one or two infections with C. difficile, and the remaining half reported three or more episodes.

Of the 402 participants whose outcomes could be analyzed, 75% reported treatment success, meaning no further C. difficile infections at 8 weeks. This was consistent with the 75% of 60 participants free of C. difficile in the interim analysis reported in 2021. Efficacy results were based on a modified intent-to-treat analysis.

Of the 300 participants who responded to RBX2660 at 8 weeks, 262 were followed up to 6 months, with 84% of these reporting no C. difficile recurrence.

“If you succeeded to 8 weeks, there was a high likelihood that you would succeed up to 6 months,” Dr. Khanna said.

For the subset of participants with inflammatory bowel disease, Dr. Khanna noted that the success rates were in the 80% range, which is higher than what is seen in clinic fecal microbiota transplantation programs.
 

Adverse events

Of the participants, 63% reported treatment-emergent adverse events. Most events were mild to moderate in severity, the researchers reported, with diarrhea and abdominal pain being the most common.

“When you look at the treatment-emergent adverse events, it’s important to put them into context in terms of this patient population,” Dr. Khanna said. “This recurrent population has developed underlying gastrointestinal symptoms like abdominal pain, diarrhea, nausea, vomiting, and weight loss.”

Some of these adverse events persist beyond resolution of the C. difficile infection, and the adverse-event profile with RBX2660 is consistent with what is seen following fecal microbiota transplantation, he added.

The serious adverse events “were very, very few,” Dr. Khanna said.

Overall, 11% of participants reported a serious adverse event. The majority were related to the C. difficile infection or an underlying comorbidity, he noted.
 

“Excruciating for patients to deal with”

Traditionally, there could be “some hesitation on the patient’s part [to undergo therapy] just because it’s delivered rectally,” session comoderator Lisa Malter, MD, said in an interview.

However, C. difficile can be “excruciating for patients to deal with,” said Dr. Malter, a gastroenterologist and professor of medicine at New York University Langone Health. They “may be more than willing to take [this agent] because it gets them feeling better.”

“This is a positive adjunct to our current therapies for C. diff in terms of trying to knock it out once a standard course of antibiotics has been administered,” she added.

Currently, people with recurrent C. difficile seek fecal microbiota material from a biobank or from a close friend or loved one.

But Dr. Malter noted that asking someone you know to donate fecal matter for transplantation requires several steps. Donors are screened to make sure they are free of gastrointestinal illness, are not taking any contraindicated medications, and do not have active infection.

Fecal microbiota samples from a biobank are more standardized, but there have been intermittent shutdowns and availability has been limited during the pandemic, she said.

Dr. Malter added that one unanswered question is how much of the colon is covered by therapy delivery via enema compared with colonoscope delivery during fecal microbiota transplantation.

“If it’s delivered colonoscopically, you get the entire colon. In contrast with an enema, you really only hit the left side of the colon,” she said.
 

FDA advisory committee nod

On Sept. 26, the Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee reviewed evidence for RBX2660. The committee voted 13 to 4 that data were adequate to support the effectiveness of RBX2660 to reduce the recurrence of C. difficile infection in adults following antibiotic treatment for recurrent infections.

Members also voted 12 to 4, with one abstention, that the data were adequate to support the product’s safety.

The FDA often follows its advisory committee recommendations but is not required to do so.

“The hope would be that this would get through the usual FDA pipeline of an approval in the near future,” Dr. Khanna said.

The study was funded by Ferring Pharmaceuticals. Dr. Khanna reported receiving grant and research funding from Ferring. Dr. Malter reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

CHARLOTTE, N.C. – RBX2660 could be a new option for people who experience recurrent, debilitating Clostridioides difficile infections.

Following a standard course of antibiotics, a one-time treatment with RBX2660 was successful for three quarters of participants at 8 weeks, according to a new study. It also prevented additional bouts, with 84% of these initial responders remaining free of C. difficile infection at 6 months.

The ongoing phase 3, open-label PUNCH CD3-OLS study expands on clinical trial experience by treating more “real-world” patients. People who might have been excluded from previous research because of comorbidities, such as irritable bowel syndrome, inflammatory bowel disease, and immunosuppression, were included.

The study also placed no limit on the number of previous rounds of C. difficile infections.

“Even when you expand the patient population to make it more generalizable, we’re still seeing both a high cure rate and a high success rate,” Sahil Khanna, MBBS, a gastroenterologist and hepatologist at the Mayo Clinic in Rochester, Minn., said in an interview.

“We also are not seeing any kind of safety signals that can be attributed to this particular product,” he said.

Dr. Khanna presented the findings during the annual meeting of the American College of Gastroenterology, which were also published simultaneously in the journal Drugs. The research by Dr. Khanna and associates received an ACG Outstanding Research Award in the colon category.
 

Study design and results

RBX2660 (Rebyota) is a microbiota-based live biotherapeutic in development from Ferring Pharmaceuticals. The treatment contains human stool collected from prescreened, qualified donors and is prepared according to good manufacturing standards.

After standard-of-care antibiotics and a 72-hour washout period, participants received a single 150-mL dose rectally by enema. RBX2660 is administered by a health care professional.

The median age of study participants was 63 years, with 45% aged 65 years or older, and 70% were women. Overall, 37% of participants had Crohn’s disease and 4% had ulcerative colitis.

At the time of screening, about half of participants had a history of one or two infections with C. difficile, and the remaining half reported three or more episodes.

Of the 402 participants whose outcomes could be analyzed, 75% reported treatment success, meaning no further C. difficile infections at 8 weeks. This was consistent with the 75% of 60 participants free of C. difficile in the interim analysis reported in 2021. Efficacy results were based on a modified intent-to-treat analysis.

Of the 300 participants who responded to RBX2660 at 8 weeks, 262 were followed up to 6 months, with 84% of these reporting no C. difficile recurrence.

“If you succeeded to 8 weeks, there was a high likelihood that you would succeed up to 6 months,” Dr. Khanna said.

For the subset of participants with inflammatory bowel disease, Dr. Khanna noted that the success rates were in the 80% range, which is higher than what is seen in clinic fecal microbiota transplantation programs.
 

Adverse events

Of the participants, 63% reported treatment-emergent adverse events. Most events were mild to moderate in severity, the researchers reported, with diarrhea and abdominal pain being the most common.

“When you look at the treatment-emergent adverse events, it’s important to put them into context in terms of this patient population,” Dr. Khanna said. “This recurrent population has developed underlying gastrointestinal symptoms like abdominal pain, diarrhea, nausea, vomiting, and weight loss.”

Some of these adverse events persist beyond resolution of the C. difficile infection, and the adverse-event profile with RBX2660 is consistent with what is seen following fecal microbiota transplantation, he added.

The serious adverse events “were very, very few,” Dr. Khanna said.

Overall, 11% of participants reported a serious adverse event. The majority were related to the C. difficile infection or an underlying comorbidity, he noted.
 

“Excruciating for patients to deal with”

Traditionally, there could be “some hesitation on the patient’s part [to undergo therapy] just because it’s delivered rectally,” session comoderator Lisa Malter, MD, said in an interview.

However, C. difficile can be “excruciating for patients to deal with,” said Dr. Malter, a gastroenterologist and professor of medicine at New York University Langone Health. They “may be more than willing to take [this agent] because it gets them feeling better.”

“This is a positive adjunct to our current therapies for C. diff in terms of trying to knock it out once a standard course of antibiotics has been administered,” she added.

Currently, people with recurrent C. difficile seek fecal microbiota material from a biobank or from a close friend or loved one.

But Dr. Malter noted that asking someone you know to donate fecal matter for transplantation requires several steps. Donors are screened to make sure they are free of gastrointestinal illness, are not taking any contraindicated medications, and do not have active infection.

Fecal microbiota samples from a biobank are more standardized, but there have been intermittent shutdowns and availability has been limited during the pandemic, she said.

Dr. Malter added that one unanswered question is how much of the colon is covered by therapy delivery via enema compared with colonoscope delivery during fecal microbiota transplantation.

“If it’s delivered colonoscopically, you get the entire colon. In contrast with an enema, you really only hit the left side of the colon,” she said.
 

FDA advisory committee nod

On Sept. 26, the Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee reviewed evidence for RBX2660. The committee voted 13 to 4 that data were adequate to support the effectiveness of RBX2660 to reduce the recurrence of C. difficile infection in adults following antibiotic treatment for recurrent infections.

Members also voted 12 to 4, with one abstention, that the data were adequate to support the product’s safety.

The FDA often follows its advisory committee recommendations but is not required to do so.

“The hope would be that this would get through the usual FDA pipeline of an approval in the near future,” Dr. Khanna said.

The study was funded by Ferring Pharmaceuticals. Dr. Khanna reported receiving grant and research funding from Ferring. Dr. Malter reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

CHARLOTTE, N.C. – RBX2660 could be a new option for people who experience recurrent, debilitating Clostridioides difficile infections.

Following a standard course of antibiotics, a one-time treatment with RBX2660 was successful for three quarters of participants at 8 weeks, according to a new study. It also prevented additional bouts, with 84% of these initial responders remaining free of C. difficile infection at 6 months.

The ongoing phase 3, open-label PUNCH CD3-OLS study expands on clinical trial experience by treating more “real-world” patients. People who might have been excluded from previous research because of comorbidities, such as irritable bowel syndrome, inflammatory bowel disease, and immunosuppression, were included.

The study also placed no limit on the number of previous rounds of C. difficile infections.

“Even when you expand the patient population to make it more generalizable, we’re still seeing both a high cure rate and a high success rate,” Sahil Khanna, MBBS, a gastroenterologist and hepatologist at the Mayo Clinic in Rochester, Minn., said in an interview.

“We also are not seeing any kind of safety signals that can be attributed to this particular product,” he said.

Dr. Khanna presented the findings during the annual meeting of the American College of Gastroenterology, which were also published simultaneously in the journal Drugs. The research by Dr. Khanna and associates received an ACG Outstanding Research Award in the colon category.
 

Study design and results

RBX2660 (Rebyota) is a microbiota-based live biotherapeutic in development from Ferring Pharmaceuticals. The treatment contains human stool collected from prescreened, qualified donors and is prepared according to good manufacturing standards.

After standard-of-care antibiotics and a 72-hour washout period, participants received a single 150-mL dose rectally by enema. RBX2660 is administered by a health care professional.

The median age of study participants was 63 years, with 45% aged 65 years or older, and 70% were women. Overall, 37% of participants had Crohn’s disease and 4% had ulcerative colitis.

At the time of screening, about half of participants had a history of one or two infections with C. difficile, and the remaining half reported three or more episodes.

Of the 402 participants whose outcomes could be analyzed, 75% reported treatment success, meaning no further C. difficile infections at 8 weeks. This was consistent with the 75% of 60 participants free of C. difficile in the interim analysis reported in 2021. Efficacy results were based on a modified intent-to-treat analysis.

Of the 300 participants who responded to RBX2660 at 8 weeks, 262 were followed up to 6 months, with 84% of these reporting no C. difficile recurrence.

“If you succeeded to 8 weeks, there was a high likelihood that you would succeed up to 6 months,” Dr. Khanna said.

For the subset of participants with inflammatory bowel disease, Dr. Khanna noted that the success rates were in the 80% range, which is higher than what is seen in clinic fecal microbiota transplantation programs.
 

Adverse events

Of the participants, 63% reported treatment-emergent adverse events. Most events were mild to moderate in severity, the researchers reported, with diarrhea and abdominal pain being the most common.

“When you look at the treatment-emergent adverse events, it’s important to put them into context in terms of this patient population,” Dr. Khanna said. “This recurrent population has developed underlying gastrointestinal symptoms like abdominal pain, diarrhea, nausea, vomiting, and weight loss.”

Some of these adverse events persist beyond resolution of the C. difficile infection, and the adverse-event profile with RBX2660 is consistent with what is seen following fecal microbiota transplantation, he added.

The serious adverse events “were very, very few,” Dr. Khanna said.

Overall, 11% of participants reported a serious adverse event. The majority were related to the C. difficile infection or an underlying comorbidity, he noted.
 

“Excruciating for patients to deal with”

Traditionally, there could be “some hesitation on the patient’s part [to undergo therapy] just because it’s delivered rectally,” session comoderator Lisa Malter, MD, said in an interview.

However, C. difficile can be “excruciating for patients to deal with,” said Dr. Malter, a gastroenterologist and professor of medicine at New York University Langone Health. They “may be more than willing to take [this agent] because it gets them feeling better.”

“This is a positive adjunct to our current therapies for C. diff in terms of trying to knock it out once a standard course of antibiotics has been administered,” she added.

Currently, people with recurrent C. difficile seek fecal microbiota material from a biobank or from a close friend or loved one.

But Dr. Malter noted that asking someone you know to donate fecal matter for transplantation requires several steps. Donors are screened to make sure they are free of gastrointestinal illness, are not taking any contraindicated medications, and do not have active infection.

Fecal microbiota samples from a biobank are more standardized, but there have been intermittent shutdowns and availability has been limited during the pandemic, she said.

Dr. Malter added that one unanswered question is how much of the colon is covered by therapy delivery via enema compared with colonoscope delivery during fecal microbiota transplantation.

“If it’s delivered colonoscopically, you get the entire colon. In contrast with an enema, you really only hit the left side of the colon,” she said.
 

FDA advisory committee nod

On Sept. 26, the Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee reviewed evidence for RBX2660. The committee voted 13 to 4 that data were adequate to support the effectiveness of RBX2660 to reduce the recurrence of C. difficile infection in adults following antibiotic treatment for recurrent infections.

Members also voted 12 to 4, with one abstention, that the data were adequate to support the product’s safety.

The FDA often follows its advisory committee recommendations but is not required to do so.

“The hope would be that this would get through the usual FDA pipeline of an approval in the near future,” Dr. Khanna said.

The study was funded by Ferring Pharmaceuticals. Dr. Khanna reported receiving grant and research funding from Ferring. Dr. Malter reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.